Amide Bond Bioisosteres: Strategies, Synthesis, and Successes
- Shikha KumariShikha KumariDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United StatesMore by Shikha Kumari,
- Angelica V. CarmonaAngelica V. CarmonaDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United StatesMore by Angelica V. Carmona,
- Amit K. TiwariAmit K. TiwariDepartment of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, Ohio 43614, United StatesMore by Amit K. Tiwari, and
- Paul C. Trippier*Paul C. Trippier*Phone: 402-836-9763. Email: [email protected]Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United StatesFred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, United StatesUNMC Center for Drug Discovery, University of Nebraska Medical Center, Omaha, Nebraska 68198, United StatesMore by Paul C. Trippier
Copyright © 2020 American Chemical Society
Abstract
The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, pKa, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.
Introduction
ARTICLE SECTIONS
The amide functional group plays a critical role in the composition of many biologically active molecules. This includes peptides and proteins, a wide variety of chemical probes and clinically approved and experimental synthetic and naturally derived drug molecules. Consequently, the amide functionality is of extreme interest to both medicinal chemists and chemical biologists.(1,2) The amide group enjoys significant attention due to its unique ability to form relevant hydrogen bonding interactions. An amide typically (the keto tautomer predominating) consists of two types of hydrogen bonding sites, the carbonyl group and the amine group, which may act as a hydrogen bond acceptor (HBA) and hydrogen bond donor (HBD), respectively.(3) The lone pair of the amine nitrogen is not available to accept a hydrogen bond due to its role in the resonance system of the functional group which installs significant conformational rigidity that further enhances or weakens the strength of the hydrogen bonds.
A peptide bond, a term erroneously used interchangeably with an amide bond, consists of an amide composed from the linkage of an α-amino nitrogen from one amino acid with the carbonyl carbon of a second amino acid. In peptide chemistry, the partial double-bond character of the amide group (due to delocalization of the lone pair of the nitrogen) results in planar geometry and thus allows adaptation of either the cis or trans conformation. In cis conformation, the two α-carbon atoms (Cα–C and N–Cα) lie on the same side of the peptide bond, whereas in the trans conformation these two carbon atoms are transposed. Nearly all proteins in their folded state adopt the trans configuration over cis to reduce steric hindrance between groups attached to the α-carbon atoms.(4)
The most common synthetic access to amides is provided by the reaction between a suitably functionalized carboxylic acid with a suitably functionalized amine, the same reaction that forms peptide bonds between amino acids to build proteins in biological systems.(5) At the bench, to increase yields, shorten reaction times, and react sterically hindered or other low reactivity substrates, the most frequently employed method for the preparation of amides involves the reaction of an activated carboxylic acid derivative, such as acid chlorides, anhydrides, or esters, with amines or alternatively, the union of carboxylic acids with amines aided by stoichiometric amounts of dedicated coupling reagents, such as carbodiimides or 1H-benzotriazole derivatives, which achieve activation of the carboxylic acid in situ.(6−9)
The role of the amide bond has gained increasing prominence in drug design and development as more detailed knowledge about its properties has been revealed in the past century. Several top-selling drugs (Figure 1) such as lidocaine (1), paracetamol (2), the penicillins (embodied by the core structure 3), atorvastatin (4), chloramphenicol (5), moclobemide (6), captopril (7), acetazolamide (8), ponatinib (9), methotrexate (10), trimethobenzamide (11), among others contain an amide functional group as part of their pharmacophore or auxophore.
Figure 1
Figure 1. Structures of selected clinically approved drug molecules containing an amide bond and their biological function.
One of the initial hurdles to overcome in the drug discovery process is the identification of a lead compound that engages a validated target in a disease of interest. In most cases, the hit compound that forms the basic structural blueprint for hit-to-lead discovery and indeed the initial lead is deficient in one or several properties required for clinical success, the required level of potency, selectivity, suitable pharmacokinetic (PK), or pharmacodynamic (PD) parameters, that impart obstacles along the path to the identification of a clinical candidate.(10) To counteract many of these issues, one of the most frequently employed strategies in hit-to-lead and lead optimization involves the replacement of a selected fragment within a compound of interest with another fragment that is known to closely mimic the properties of the original fragment or functional group. This process of replacement or modification of functional groups, having similar properties, is known as isosteric or bioisosteric replacement and has become a mainstay of the medicinal chemist’s toolbox.(11−13)
Bioisosterism is considered a qualitative technique to achieve the rational modification and optimization of a bioactive compound that can provide several beneficial effects including increased potency, enhanced selectivity, improvements in PK and PD properties, elimination or attenuation of toxicity and facilitate access to novel chemical space to attain patent protection.(14) Bioisosteres can be categorized into classical and nonclassical subtypes. Classical bioisosteres are functional groups that satisfy Grimm’s hydride displacement law as well as Erlenmeyer’s concepts of isosteres and can be subdivided into five categories: (a) monovalent atoms or groups, (b) divalent atoms or groups, (c) trivalent atoms or groups, (d) tetravalent atoms or groups, and (e) ring equivalents (Table 1). On the other hand, nonclassical bioisosteres possess more advanced mimicry of their emulated counterparts and do not fulfill the criteria of steric and electronic factors required for classical isosteres (Table 1).(15−17,11)
Table 1. Classification of Classical and Nonclassical Bioisosteres
| Classical bioisosteres | Nonclassical bioisosteres |
|---|---|
| a. Monovalent atoms or groups F and H; D and H; NH and OH; C and Si; RSH and ROH; -F; -Cl; -Br; -I; −OH; -OR; -SH; -PH2; -CH3; -CF3; -NH2 | a. Rings versus acyclic structures. Methyleneaminoxy methyl moiety (C═NOCH2, MAOMM) as a bioisostere of aryl and other aromatic scaffold. |
| b. Divalent atoms or groups -O-; -Se-; -CH2-; -C═N-; -C═S; -C═C-; -C═O; -C═NH; -COOR; -COSR; -CONHR; -COCH2R | b. Exchangeable groups, hydroxyl group bioisosteres, carbonyl group bioisosteres, amide group bioisosteres, thiourea group bioisosteres, halogen group bioisosteres, carboxylate group bioisosteres |
| c. Trivalent atoms or groups -As═; -N═; -P═; -CH═ | |
| d. Tetravalent atoms or groups ═C═; ═Si═ ; ═As+═; ═N+═; ═P+═ | |
| e. Ring equivalents benzene; tetrahydrofuran; thiophene; pyridine |
The installation of a bioisostere leads to structural changes that can be either beneficial or deleterious to biological activity depending upon the effect on overall molecular size, shape, electronic distribution, lipophilicity, dipole moment, and polarizability.(16) For example, the tetrazole heterocycle is a well-known bioisostere of a carboxylic acid.(18) Several studies have demonstrated that the 1,2,3-triazole moiety is an amide surrogate.(19) The utilization of this approach has opened new avenues in drug design and development, resulting in more efficient drug candidates that have reached the clinic as well as countless numbers in the pipeline.
The amide functional group is enzymatically very labile in vivo; therefore, amide bond bioisosteres that improve metabolic stability are of great interest, particularly for applications in peptide chemistry and the development of peptidomimetics.(20) Peptide drugs represent a major class of pharmacologically active compounds, composed of small molecules and proteins that have been deployed to treat cancer, diabetes, infectious diseases, and cardiovascular diseases among other indications.(21−23) The U.S. Food and Drug Administration (FDA) has approved over 60 peptide drugs, and approximately 140 new peptide therapeutics are currently being evaluated in clinical trials at the time of writing.(24) Although peptides are endowed with high specificity and low toxicity and are generally well-tolerated in humans, many therapeutic peptides suffer from poor metabolic stability due to the rapid degradation of the amide bond by proteases.(25,26) Thus, the introduction of structural motifs that mimic the physicochemical properties of the amide bond provides greater metabolic stability. The replacement of the amide bond by a bioisostere can afford new peptidomimetics with improved biological properties and retention of the desired therapeutic effect. To date, several amide bioisostere classes are known, including 1,2,3-triazole, oxadiazole, imidazole, tetrazole, pyrazole, indole, pyridine, pyrazine, retroinverted and reverse amide, urea, olefin, fluoroalkene, trifluoroethylamine, amidine, ester, sulfonamide, phosphonamidate, thioamide, and carbamate. The past decade has seen enormous success in the application of these amide bioisosteres in the construction of more sophisticated and often more active compounds. Choosing the most appropriate bioisostere is a complex task. Consideration of feasible synthetic routes, modification strategies, and bioactivity effects of prior successes in the field of amide bioisosteric replacement can provide valuable insights into drug discovery projects.
There are a number of prior articles available in the literature that discuss the application of several types of classical and nonclassical bioisosteres in drug design(27−31) along with a more recent review focused on amide bioisosteres.(32) This Perspective aims to be a reference guide for medicinal chemists to peruse a selection of the most common amide bond bioisosteres and make an informed choice on a potentially appropriate moiety to employ in their project, with the caveat that any hit or lead compound of interest will possess distinct properties that may preclude some or all of the highlighted bioisosteres from either a synthetic or biological perspective. We review a broad range of amide bioisosteres covering their successful design, application of modification strategies, bioisosteric relationships, and pharmacological advancements along with a summary of synthetic methodologies adopted to access more potent therapeutic agents. In this context, we have categorized amide bioisosteres into 13 categories: heterocycles, retroinverted and reverse amide, urea, carbamate, amidine, thioamide, trifluoroethylamine, sulfonamide, phosphonamidate, ester, olefin, fluoroalkene, and finally miscellaneous bioisosteres.
Five-Membered Ring Heterocycles as Amide Bioisosteres
ARTICLE SECTIONS
A. Triazole
The triazole moiety has repeatedly shown potential application in refining the therapeutic ability of amide bond-containing molecules and therefore is considered an excellent nonclassical bioisostere. Most importantly, the triazole motif is proficient in mimicking the configuration of the trans amide bond; either a trans or a cis conformation can be achieved around the heterocycle depending on the substitution pattern of the triazole.(33) The 1,4-disubstituted 1,2,3-triazole scaffold is isosteric to the trans amide bond and has gained widespread use (Figure 2). The 1,5-disubstituted 1,2,3-triazole moiety mimics the cis amide bond, and its use is much less common.(34) The distance between the substituents at the 1- and 4-position of the triazole ring is 5.0–5.1 Å, which is approximate to the 3.8–3.9 Å distance between trans amide substituents.(35) Several fundamental properties, such as planarity, dipole moment and hydrogen bonding properties of the 1,2,3-triazole, are comparable to those of an amide.
Figure 2
Figure 2. Representative structures of the trans and cis amide mimics 1,4-disubstitued 1,2,3-triazole and 1,5-disubstitued 1,2,3-triazole respectively, highlighting their distancing and hydrogen bonding capabilities.
Similarly, the dipole moment of the amide (∼4 D) and 1,2,3-triazole (∼5 D) is not significantly different.(36) The two indicated nitrogen atoms (Figure 2) in the triazole moiety possess lone pairs of electrons that act as hydrogen bond acceptors, playing a similar role as the oxygen atom in the amide. The CH bond within the triazole exhibits a strong dipole moment and therefore can function as a hydrogen bond donor, analogous to the amide NH.(37) The 1,2,3-triazole unit is particularly resistant to cleavage mediated by proteases, oxidation, and hydrolysis.(38) In summary, the 1,2,3-triazole moiety possesses characteristics that could afford protease-resistant peptidomimetics with retained or even improved biological activity. Much literature has been published in recent years that have shown the advantages of the 1,2,3-triazole moiety.(19) Successful replacement of the amide bond within bioactive scaffolds with a 1,2,3-triazole has led to the discovery of many potent bioactive molecules, including approved marketed drugs to combat human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), bacterial infections, cancer, and neurological disorders.
The Rana research group has investigated the RN-18 class of small molecules to target HIV-1 accessory protein viral infectivity factor (Vif) to identify novel antagonists.(39−41) The 23 kDa Vif protein is critical for in vivo viral replication and has emerged as a validated target for HIV-1/AIDS drug development.(42,43) Initially, the group had identified a lead compound RN-18 (12, Figure 3) that specifically antagonizes HIV-1 Vif protein function [in H9 (nonpermissive cells), IC50 = 6 μM] and obstructs viral replication. Compound 12 does not inhibit viral infectivity in permissive cells, MT4 (human T-lymphoid cells), even at 100 μM which highlights its Vif specificity.
Figure 3
Figure 3. Replacement of the amide bond in RN-18 (12) with a 1,2,3-triazole moiety to afford compound 13 (1-2-methoxyphenyl)-4-(2-((4-nitrophenyl)thio)phenyl)-1H-1,2,3-triazole).
However, two significant concerns related to the potency and metabolic stability of RN-18-based Vif antagonists became an obstacle to further clinical development. In a follow-up study, the authors used the concept of bioisosterism and replaced the amide bond in 12 with 2,5-disubstituted-1,3,4-oxadiazole, 3,5-disubstituted-1,2,4-oxadiazole, 1,4-disubstituted-1H-1,2,3-triazole, or 1,5-disubstituted-1H-1,2,3-triazole moieties, aiming to improve the pharmacological profile. In the original paper, the authors did not comment on any structural role for the amide in 12. However, they synthesized new analogs that were tested in vitro using wild-type HIV-1 in both H9 and MT-4 cells. Results of this experiment have shown that the installation of only the 1,4-disubstituted-1,2,3-triazole moiety (compound 13; IC50 = 1.2 μM; H9 cells, Figure 3) as an amide bond bioisostere resulted in increased potency over the parent compound (IC50 = 6 μM; H9 cells). The general synthetic method (i) to access compound 13 through the application of copper catalyzed azide–alkyne cycloaddition (CuAAC) click chemistry is delineated in Scheme 1, i. Overall, compound 13 was determined to be a potent Vif antagonist. Inspired by the obtained results, a subseries of new triazole containing analogs (based on 13) was also synthesized that resulted in the discovery of more potent HIV-1 inhibitors than compound 13 itself.(44)
Scheme 1
Scheme 1. General Synthetic Pathway To Access Triazole Scaffold via Copper(I)-Catalyzed Azide–Alkyne Cycloaddition Click Chemistry
Vismodegib (GDC-0449, compound 17) is a highly specific small molecule synthetic smoothened (SMO) antagonist that inhibits the Hedgehog (Hh) signaling pathway, upregulated in basal-cell carcinoma (BCC).(45) Compound 17 was approved by the FDA in 2012 to treat locally advanced and metastatic unresectable BCC. Several clinical studies indicated that many BCC patients experienced substantial benefits from 17; however, they developed side effects including muscle spasms, alopecia, dysgeusia, fatigue, and weight loss.(46,47) Additionally, patients acquired resistance upon treatment with compound 17, which was associated with Hh pathway reactivation.(48) Considering these problems, Passarella and colleagues modified the structural framework of compound 17, aiming to improve potency as well as other pharmacological features.(49) Initially, a virtual library of 140 triazole-containing derivatives were screened. On the basis of the obtained docking results, several analogs were synthesized wherein a 1,2,3-triazole bioisostere was introduced in place of the amide of compound 17, along with additional alterations of the substituents on the phenyl rings (Figure 4).
Figure 4
Figure 4. Example of amide versus 1,2,3-triazole bioisosterism in vismodegib (17), a potent Hh signaling pathway inhibitor.
The in vitro antiproliferative activity of all synthesized compounds was determined in three cancer lines (L1210, murine leukemia cells; CEM, human T-lymphocyte cells; HeLa, human cervix carcinoma), and two endothelial cell lines (HMEC-1, human microvascular endothelial cells; BAEC, bovine aortic endothelial cells). Compound 18 possessing the 1,2,3-triazole ring in place of the amide bond (17) displayed an appreciable activity benefit in HMEC-1 cells (IC50 = 9.6 ± 0.7 μM) as compared to parent 17 (IC50 = 41 ± 3 μM). Thus, it can be considered that the triazole ring is solely responsible for lowering IC50 in this context. The most potent compound of the series 19, containing further structural changes beyond the bioisostere, possessed greater influence on all tested cell lines compared with compound 17 (Figure 4). The general synthetic method (i) to obtain compounds 18 and 19 is depicted in Scheme 1, i. Overall, results suggested the 1,2,3-triazole scaffold provided favorable bioactivity outcomes on this pharmacophore.
In another study, the Passarella group synthesized triflorcas and a close analog containing a 1,2,3-triazole as an amide bond surrogate. In silico docking studies showed that the -NH-CO- function is involved in hydrogen bonding with Glu1127 and Lys1110 in the same way that the triazole ring is stabilized by polar interactions with Lys1110. Overall, docking results confirmed the binding of the 1,2,3-triazole bioisostere into the adenosine triphosphate (ATP) binding site of N-methyl-N′-nitrosoguanidine human osteosarcoma transforming gene (MET) in a similar fashion as triflorcas. Results of hepatocyte growth factor (HGF)-induced scattering of Madin–Darby canine kidney (MDCK) epithelial cells and in vitro tumorigenesis of H1437 cells (non-small-cell lung cancer) and GTL-16 cells (human gastric carcinoma) showed that the 1,2,3-triazole bioisostere was nearly equipotent with triflorcas. The overall results of this study suggest that the replacement of the amide bond with 1,2,3-triazole ring maintained the tumorigenesis inhibitory potential of the lead compound triflorcas.(50−52)
Imatinib is a tyrosine-kinase inhibitor that is approved for the treatment of chronic myelogenous leukemia (CML), certain types of gastrointestinal stromal tumors (GIST), and a number of other malignancies.(53−57) The development of resistance to imatinib called for the need to develop small molecule inhibitors that could overcome imatinib resistant in CML patients.(58) Passarella and colleagues reported the first example of amide bioisosterism in imatinib via a 1,2,3-triazole. Among all tested analogs, the most potent compound (FA030; structure not shown) possessing the 1,2,3-triazole motif in place of the amide bond of imatinib showed similar binding patterns in molecular modeling studies. FA030 displayed potent antienzymatic activity against recombinant Abl kinase but decreased activity in the imatinib-resistant mutant Abl T3151. In addition to this, FA030 decreased the phosphorylation of break point cluster region Abelson kinase (Bcr-Abl), c-Abl, signal transducer and activator of transcription 5 (STAT-5), and Src, a protooncogene encoding a non-receptor tyrosine kinase in a dose-dependent manner similar to imatinib.(52)
Modulation of the dopamine-3 subtype receptor (D3-R) influences neuronal activity in some parts of the brain; therefore, the D3-R has gained special attention in the development of therapeutics to treat neurological diseases such as schizophrenia, Parkinson’s disease (PD), and associated dyskinesias, as well as neuropsychiatric (particularly drug addiction) disorders.(59,60) The development of selective D3-R ligands is an extremely challenging task due to their very close homology with dopamine-2 subtype receptor (D2-R).(61) The Hauck Newman group discovered PG648 (20), OMO5-057 (21), and NGB2904 (22) as highly potent and selective D3-R ligands (Figure 5).(62,63)
Figure 5
Figure 5. Molecular structures of highly potent D3-R ligands: 20, 21, 22 containing amide; 23, a 1,2,3-triazole analog.
Prior structure–activity relationship (SAR) studies disclosed a molecular sketch design that consists of an amalgamation of two pharmacophores, a phenylpiperazine moiety and an extended aryl ring unit, linked via a butyl chain essential to produce D3-R partial agonism/or antagonism.(64) Moreover, the amide function provided a necessary element to impart maximum D3-R over D2-R selectivity.(65) Although 20, 21, and 22 have shown potent D3-R binding affinity, their poor metabolic stability, mainly due to the presence of the amide, has impeded translation of these candidates to clinical use. To resolve this issue and in an effort to find more potent and D3-R selective ligands, a library of structurally modified analogs of 20, 21, and 22 were synthesized, in which the amide bond was replaced with a 1,2,3-triazole scaffold to generate a library of compounds.(66)
In this context, a 1,2,3-triazole was tested as a bioisosteric surrogate for the amide group in a series of compounds consisting of a substituted phenylpiperazine connected via an appropriate carbon linker to an aryl unit, with synthetic access provide by CuAAC click chemistry (Scheme 1, ii). This modification led to the discovery of compound 23, which showed promising D3-R binding affinity and 165-fold selectivity over the D2-R, evaluated by radioligand competition binding experiments using human embryonic kidney 293 (HEK293) cells, expressing human dopamine receptor subtypes. Compound 23 displayed better metabolic stability (35%) toward mouse liver microsomes (MLM) in phase 1 metabolic stability assay experiments than 20 (11%), remaining after 1 h incubation. Thus, it indicated that 1,2,3-triazole containing molecules could provide specific resistance to CYP450-mediated phase 1 metabolism over amide bioisosteres.
In a study aiming to replace an amide linker that would be capable of sustaining and modulating amide-related bioactivity, structural modifications to capsaicin (24) were explored in the context of a 1,2,3-triazole group as a bioisosteric element (Figure 6).(67) The vanilloid and cannabinoid (CB) profiles of synthesized analogs were compared with compound 24 and other capsaicinoids. Success was achieved with compound 25, which presented antagonistic activity for vanilloid receptor 1, transient receptor potential cation channel subfamily V member 1 (TRPV1) with an IC50 of 0.69 ± 0.16 μM (found inactive as TRPV1 agonist with EC50 > 10000 nM and therefore tested as a TRPV1 antagonist). Compound 25 was synthesized by using copper iodide (CuI) catalyzed click chemistry as shown in the Scheme 1, iii. This compound also showed a significant submicromolar affinity for human cannabinoid 1 (hCB1) (Ki = 0.44 μM), the psychotropic cannabinoid receptor. In conclusion, the installation of a 1,2,3-triazole ring within the pharmacophore of compound 25 resulted in potent TRPV1 and CB1 selective antagonist activity. The authors in the original paper commented on the usefulness of compound 25 as a dual and unique TRPV1/CB1 antagonist; however, there was no mention that this was due solely to the 1,2,3-triazole bioisostere.
Figure 6
Figure 6. 1,2,3-Triazole as an amide bond bioisostere in a TRPV1/CB1 antagonist.
An example of developing potent and selective cannabinoid-2 (CB2) receptor ligands using a bioisosteric approach was reported by Corelli and co-workers.(68) Ligands selective to the CB2 receptor are desirable for treating pain associated with inflammation, cancer, and neuropathic conditions, which avoids the unwanted psychoactive effects typically induced by activation of the cannabinoid-1 (CB1) receptor.(69−71) Aiming to optimize the physicochemical properties of a previously developed lead (26), the authors experimented with different heteroaromatic rings as amide surrogates in a series of 4-quinolone,3-carboxylic acid derivatives. The 1,2,3-triazole ring in 27 was prepared by microwave-assisted, CuI-catalyzed azide–alkyne 1,3-dipolar cycloaddition (Scheme 1, iv). The installation of a 1,2,3-triazole motif in place of the amide bond led to the development of the most potent compound among the series, 27 (Figure 7). This compound resolved solubility issues present in the lead compound (26) and also showed attractive results in in vitro CB1 and CB2 binding assays.
Figure 7
Figure 7. Molecular structure of lead compound 26 and its bioisostere 27.
A series of novel α-lipoic acid (LA) derivatives tethered to a chroman ring were designed, where the amide bond in previously synthesized analogs(72) was replaced with several five-membered heterocyclic amide isosteres to study effects on the neuroprotective activity (Figure 8).(73) Compound 29 possessing a 1,2,3-triazole was obtained by CuAAC click chemistry, as illustrated in Scheme 1, i.
Figure 8
Figure 8. Structural transformation of parent compound 28 into 29 illustrating amide/triazole bioisosterism.
α-Lipoic acid or 1,2-dithiolane-3-pentanoic acid, reported as a therapeutic agent against oxidative stress models of death, and its structural analogs were found to be effective against reperfusion arrhythmias,(74) acetylcholinesterase inhibition,(75) butyrylcholinesterase inhibition,(76) and nitric oxide synthase inhibition.(77) Several studies also showed LA analogs as potent antiproliferative(78−80) and anti-inflammatory agents.(81) Results of neuroprotective activity experiments showed that bioisosteric replacement of the amide group in compound 28, by a 1,2,3-triazole (29), improved glutamate induced oxidative stress in mouse hippocampal neurons (HT22), EC50 = 2.10 ± 0.40 μM and EC50 = 0.90 ± 0.04 μM, respectively. In Figure 8, the relative potency was calculated by EC50 of standard/EC50 of tested compound, whereas the % efficacy was calculated at a fixed concentration of 10 μM (compounds were considered to be fully, partially, or weakly neuroprotective if % efficacy is >66–100%, >33–66%, and ≤33%, respectively). The SAR analysis revealed that the presence of a nitrogen heterocycle was mostly well tolerated and strongly influenced the neuroprotective activity of 5-substitued chroman derivatives, depending on the nature of the heterocycle.
An example wherein the 1,2,4-triazole was successfully installed as an amide bioisostere within a rigid ring system is found in the short-acting benzodiazepine alprazolam (31) (Figure 9). Benzodiazepines are a class of drugs used as anxiolytics, sedative-hypnotics, anticonvulsants, and muscle relaxants and have achieved significant economic success.(82,83) This interesting journey started in 1963 when diazepam (30) was discovered and later approved for clinical use to treat anxiety, epilepsy, muscle spasms, and alcohol withdrawal symptoms.(84−86) Compound 30 is a potent orally bioavailable central nervous system (CNS) penetrant small molecule, acting predominantly via positive allosteric modulation of γ-aminobutyric acid A (GABAA) chloride channels in the brain.(87)
Figure 9
Figure 9. Replacement of an amide moiety with a 1,2,4-triazole: diazepam (30) to alprazolam (31).
In humans, 30 is metabolized by the liver cytochrome (CYP) P450 enzyme system into three pharmacologically active metabolites (Figure 10). Demethylation of 30 by CYP 2C9, 2C19, 2B6, 3A4, and 3A5 yields N-desmethyldiazepam/nordazepam (32), which is then oxidized to oxazepam (33). This metabolite 32 is a major circulating active metabolite (half-life of 50–120 h) equipotent to 30. As seen in Figure 10, the oxidation at C3 of 30 by CYP 3A4 and CYP 3A5 led to temazepam (34). The end product of 30 metabolism is 33 which is excreted in the urine. Each of these metabolites has a half-life of more than 24 h which in turn causes diazepam-induced toxicity. Subsequently, 33, 32, and 34 were developed and marketed as individual drugs.(88)
Figure 10
Figure 10. Metabolic transformation of diazepam (30) into three active metabolites: desmethyldiazepam/nordazepam (32), oxazepam (33), and temazepam (34).
In 1971, Hester and co-workers reported several close analogs of 30, including 31, wherein the amide functionality was replaced with a triazole moiety. Compound 31 was synthesized by refluxing 7-chloro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepine-2-thione (35) with acethydrazide in n-butanol (Scheme 2) for 4 h.(89) This compound was evaluated in vivo using CF-1 male albino mice and was found to be more potent than the parent, compound 30, in a variety of pharmacological assays. A few years later, 31 was approved by the FDA for the treatment of anxiety disorders. Human PD studies indicated that 31 did not produce active metabolites, resulting in significant suppression of diazepam-induced toxicity.(90)
Scheme 2
Scheme 2. Synthesis of the Benzodiazepine Compound Alprazolam (31) from 7-Chloro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepine-2-thione (35)
B. Oxadiazoles
Oxadiazoles are members of the azole class of heterocycles composed of two carbons, two nitrogens, and one oxygen atom. The oxadiazole ring exists in several different regioisomeric forms: 1,2,4-isomers (two forms), 1,3,4-isomer (one form), and 1,2,5-isomer (one form) (Figure 11).(91)
Figure 11
Figure 11. Different regioisomeric forms of the oxadiazole ring.
The oxadiazole moiety is a weak base because of the inductive effect of the extra heteroatom. Electrophilic substitutions at the carbon atom of the oxadiazole ring are difficult to accomplish due to the low electron density on the carbon atom, attributed to the electron withdrawing effect of the pyridine-type nitrogen. Electrophilic attack occurs at the nitrogen if the oxadiazole ring is substituted with an electron donating group (EDG). Oxadiazoles are largely resistant to nucleophilic attack but can undergo nucleophilic substitution in the same manner as an aliphatic sp2 carbon. These highlighted physicochemical properties of the oxadiazole motif impart versatility for its use in medicinal chemistry, and it has been utilized in the discovery of potent anti-HIV, anticancer, antimicrobial, anti-inflammatory, antidiabetic, and antiobesity agents.(92) Moreover, several oxadiazole-containing molecules are known as D3-R ligands,(93) benzodiazepine receptor agonists,(94) muscarinic receptor agonists,(95) monoaminoxidase B inhibitors,(96) selective adenosine A2B receptor antagonists,(97) and 5-hydroxytryptamine (5-HT) receptor antagonists.(98)
Improved metabolic stability, membrane permeability, and bioavailability may be achieved with oxadiazoles, and they are often used as amide bioisosteres.(92,99) Among the different regioisomeric forms, the 1,2,4-isomer and 1,3,4-isomer are most commonly employed in the bioisosteric replacement of an amide bond.(100) Both of these isomers can mimic the molecular planarity and dipole moment of an amide, but being a nonclassical amide bioisostere, the heterocycle shows variation in aromatic, electrostatic, and hydrogen bonding character.(101)
Researchers at Bristol-Myers Squibb evaluated the 1,2,4-oxadiazole ring as a bioisostere for the amide functionality within compound 36, which provided BMS-708163 (37), a compound that proved to have potent as well as selective inhibition for γ-secretase and possessed excellent PK properties in animal models as compared to the parent (Figure 12).
Figure 12
Figure 12. Amide bioisosteric replacement with an oxadiazole ring leading to a potent and selective γ-secretase inhibitor.
The abnormal aggregation of the amyloid-β (Aβ) peptide is a known hallmark of Alzheimer disease (AD). Inhibition of γ-secretase is being explored to lower Aβ production in the AD patient’s brain.(102) The γ-secretase enzyme also plays an essential role in the Notch signaling pathway, and the normal functioning of this pathway is important for proper development in all multicellular organisms.(103,104) Therefore, the identification of a γ-secretase inhibitor with no effects at the Notch receptor is desirable.(105)
The oxadiazole moiety of compound 37 was introduced as depicted in Scheme 3, i. In vitro evaluation showed that compound 37 potently inhibited both Aβ40 (IC50 = 0.30 ± 0.15 nM (mean ± SD) and Aβ42 (IC50 = 0.27 ± 0.12 nM) cleavage in H4-8Sw cells. As designed, this compound demonstrated poor potency for Notch inhibition. Even though the parent amide-containing compound 36 showed potent γ-secretase inhibition, it possessed poor metabolic stability, indicating the potential for rapid in vivo clearance. In contrast, the replacement of the enzymatically labile amide bond with the oxadiazole ring significantly improved the metabolic stability of 37 [% remaining after 10 min of incubation is 32% (rat), 75% (dog), and 97% (human)]. Moreover, upon oral administration compound 37 notably reduced Aβ40 levels in the brain, plasma, and cerebrospinal fluid in both rats and dogs.
Scheme 3
Scheme 3. General Synthetic Route To Obtain the 1,2,4-Oxadiazole Moiety from an Amidoxime
In search of new structural lipoic acid (LA) analogs as potent neuroprotective agents, a set of 1,2-dithiolane/chroman hybrids was designed and synthesized by Koufaki et al.(73) Compound 28 is an amide-containing LA structural analog which was previously reported (Figure 13).(72) Initially, this compound was found to be effective against reperfusion arrhythmias and was included in this study to check its neuroprotective ability. To explore the SAR, the amide bond in 28 was replaced by different amide bioisosteres (triazole isostere 29 is discussed previously in the 1,2,3-triazole section). The general synthetic method to obtain a 1,2,4-oxadiazole bioisostere (40, Scheme 3, ii) was achieved by intermolecular cyclization of respective acyl amidoxime in the presence of tetrabutylammonium fluoride (TBAF). The neuroprotective potential of both compounds (28 and 40) was assessed in HT22 cells, challenged with glutamate to mediate excitotoxicity, which in turn could mimic cytotoxic conditions arising due to oxidative stress in AD and other neurodegenerative disorders. Compound 40 demonstrated substantial improvement in activity against glutamate-induced oxidative stress in HT22 cells (Figure 13) as compared to parent 28.
Figure 13
Figure 13. Structures of parent amide-containing α-lipoic acid analog 28 and its 1,2,4-oxadiazole bioisostere 40.
In another study reported by Koufaki et al., an amide bond replacement on chroman linked with two methylene carbons to a 3,4-dimethoxyphenyl ring (41) was used in the identification of a potent neuroprotective agent (Figure 14).(106) Compound 42 bearing a 1,2,4-oxadiazole moiety was synthesized by following the general procedure as shown in Scheme 3, ii. Results of the in vitro evaluation of newly synthesized analogs, using glutamate-challenged HT22 cells, showed that several compounds displayed good neuroprotective ability, but among all, compound 42 demonstrated notable neuroprotection (EC50 = 254 ± 65 nM). Hence, the amide replacement with 1,2,4-oxadiazole proved to be successful in protecting neuronal cells from oxidative stress-induced cell death.
Figure 14
Figure 14. Structures of parent chroman analog 41 and its 1,2,4-oxadiazole bioisostere 42.
Another example describing the potential of the oxadiazole ring as an amide surrogate was published by the Lindsley group, aiming to discover potent metabotropic glutamate receptor subtype-7 negative allosteric modulators (mGlu7-NAMs).(107) Initially, two compounds 43 and 44 were identified as potent mGlu7-NAMs.(108,109) Both 43 and 44 displayed strong efficiency for the mGlu7-receptor, but their poor metabolic stability attributed to the amide linker hindered their further development (Figure 15). The authors decided to replace the amide linker with several amide bioisosteres. Success was achieved with the identification of a 1,3,4-oxadiazole in compound 45(107) (Figure 15) that not only demonstrated potent mGlu7-NAM activity but also showed favorable plasma protein binding (rat fu = 0.10), low predicted hepatic clearance in microsomal incubations (rat CLhep = 27.7 mL min–1 kg–1), and high CNS penetration (rat Kp = 4.9, Kp,uu = 0.65); however, the authors did not mention the CNS penetration properties (rat fu and rat Kp) for the parent amides 43 and 44. Compound 45 exhibited a favorable selectivity index over another seven mGlu receptors (>10 μM vs mGlu1–6, 8). As shown in Scheme 4, 2-(1H-imidazol-1-yl)-5-(trifluoromethoxy)benzoic acid (46) undergoes a propylphosphonic anhydride mediated microwave-assisted condensation of 3,4-dimethoxybenzohydrazide acid to furnish 45.
Figure 15
Figure 15. Structures of parent amides 43 and 44, potent mGlu7-NAMs and the 1,3,4-oxadiazole bioisostere 45.
Scheme 4
Scheme 4. Synthetic Preparation of 45, a Potent and Selective mGlu7-NAM
The replacement of an amide with different isomeric forms of oxadiazole has been employed to improve metabolic stability of the parent compound in numerous bioactive compounds. One efficient example of this is found in β-homophenylalanine-based dipeptidyl peptidase enzyme inhibitors.(110) The inhibition of dipeptidyl peptidase-4 (DPP-4) is linked to augmentation of the biological activity of the “incretin” hormones (glucagon-like peptide 1; GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which in turn is responsible for diminishing the pathophysiological symptoms of diabetes.(111) Hence, DPP-4 inhibitors, or gliptins, emerged as a promising therapeutic target for novel oral antihyperglycemic agents. Initially, the Santhera group discovered β-homophenylalanine pyrrolidine-2-ylmethylamide derivative (47), a potent as well as selective DPP-4 inhibitor (Figure 16). Unfortunately, 47 suffered from high efflux ratio and low Caco-2 permeability, accounting for its poor PK properties. The bioisosteric replacement of the problematic amide employed a 1,2,4-oxadiazole and related heterocycle. Some success was achieved with the identification of two different isomeric oxadiazole containing compounds (48 and 49). Both compounds were found to be nearly equipotent with the parent (47) in DPP-4 inhibition assays, with slight improvement in vitro metabolic stability. Therefore, on the basis of these obtained biological results, new analogs containing an isomeric oxadiazole moiety with different substituents, which could provide long plasma half-lives to the molecule, were designed and synthesized. The adopted drug modification approach proved efficacious and led to the development of 50 and 51, which showed excellent DPP-4 inhibitory potential in vitro and improved oral glucose tolerance in ob/ob mice and also exhibited attractive PK profiles (Figure 16). The synthetic methods for the preparation of both 50 and 51 are depicted in Scheme 5.
Figure 16
Figure 16. Structural optimization in the development of potent DPP-4 inhibitors to treat type 2 diabetes mellitus.
Scheme 5
Scheme 5. Synthetic Preparation of 50 and 51, Potent DPP Inhibitors
The final reaction in mammalian triglyceride synthesis is catalyzed by two acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes (DGAT-1 and DGAT-2); out of these, inhibition of DGAT-1 is known as a feasible strategy for the treatment of diabetes and obesity.(112) Recently, researchers at the Novartis Institutes of Biomedical Research have explored the 1,3,4-oxadiazole moiety as an amide bioisostere (56, Figure 17) in search of new potent DGAT-1 inhibitors.(113)
Figure 17
Figure 17. Lead optimization journey to discover a potent and orally bioavailable DGAT-1 inhibitor.
Initially compound 56, a benzimidazole derivative containing an amide linker joining the western phenyl ring, was determined to be a potent inhibitor of DGAT1.(114) Besides its potent DGAT-1 inhibitory activity (IC50 = 39 nM; C2C12 mouse myoblast cellular assay), this compound has shown a low A–B value (0.7 × 10–6 cm/s) in the Caco-2 permeability assay and a low oral bioavailability profile in vivo. To improve membrane permeability and reduce efflux of the parent 56, the initial structural changes comprised bioisosteric replacement of the amide in 57 with oxazole (58) and oxadiazole (59), along with modifications on the carboxylic acid-containing fragment. The SAR studies revealed that replacement of the amide with oxazole and oxadiazole moieties, combined with removal of the propionic acid moiety, provided potent DGAT1 inhibition (Figure 17). On the basis of this SAR, the oxadiazole moiety was chosen as the amide surrogate to incorporate into this particular chemotype. The general synthetic method to furnish 1,3,4-oxadiazole bioisostere (as in 60) using Burgess reagent is shown in Scheme 6, i. Overall, these efforts lead to the development of a benzimidazole derivative containing a 1,3,4-oxadiazole moiety, 60, which displayed excellent DGAT-1 inhibition (Figure 17). Moreover, this compound desirably showed poor inhibition for DGAT-2 (IC50 > 10 μM) and a low risk of mutagenicity in the Ames assay. Compound 60 suppressed postprandial plasma triglycerides in a dose-dependent manner in healthy human subjects.
Scheme 6
Scheme 6. General Synthetic Route for Preparing 1,3,4-Oxadiazole from Diacylhydrazine
In the optimization of a series of previously identified 6-substituted 4-quinolone-3-carboxamides as highly selective and potent CB2 receptor ligands by Corelli and colleagues,(115) the poor solubility profile of these compounds which hampered biological assays led to the use of a bioisosteric approach to give high-affinity CB2 receptor ligands with good selectivity, along with acceptable physicochemical properties. In a follow-up study, the amide bond present in the central core of the parent compounds(116,117)63 and 64 was replaced by three different amide surrogates: a 1,2,3-triazole, a 1,3,4-oxadiazole, and a 1,2,4-oxadiazole. Second, the quinolone ring was also substituted with 2-furyl, 4-bromo, and 4-isopropoxyphenyl moieties to derive the SAR (Figure 18).(68)
Figure 18
Figure 18. Bioisosteric amide replacement via 1,3,4-oxadiazole (65) and 1,2,4-oxadiazole (66) in a series of CB2 receptor ligands.
Results of this experiment showed that the 1,2,3-triazole-containing derivative 27 (discussed in the 1,2,3-triazole section above) emerged as the most potent CB2 receptor ligand with promising PD and physicochemical properties. Apart from this, the 1,3,4-oxadiazole (65) and 1,2,4-oxadiazole (66) derivatives showed notable CB2 receptor binding affinity of 6.5 ± 2.2 nM and 0.4 ± 0.1 nM, respectively (Figure 18). Unfortunately, the latter (66) exhibited poor selectivity over the CB1 receptor (80-fold), while compound 65 was nearly 1500-fold more selective to the CB1 receptor over CB2. Overall results were compared with lead compound 26, which showed potent CB2 receptor binding affinity with 14,000-fold selectivity over CB1 receptor. The general synthetic routes to access compounds 65 and 66 are shown in Scheme 6, ii, and Scheme 3, iii, respectively.
C. Imidazole
Arguably the most successful example of amide versus imidazole bioisosterism is presented in the discovery of midazolam (67) at Hoffmann-LaRoche, Inc., U.S.(118) Compound 67 or 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine is a structural analog of 30, in which the amide bond has been successfully replaced by an imidazole moiety (Figure 19). This structural modification increased the basicity of the molecule due to the imidazole ring nitrogen, which allowed the formation of water-soluble salts for pure aqueous injectables.(119) Moreover, it undergoes rapid metabolic inactivation as compared to 30 and the other classical benzodiazepines which is attributed mainly to the presence of the methyl group appended to the imidazole ring. This results in a short window of action allowing greater clinical management options.
Figure 19
Figure 19. Structures of diazepam and the imidazole-containing analog midazolam.
Very recently, Taghizadeh et al. reported a one-pot condensation of benzodiazepines with the monoanion of tosylmethyl isocyanide or ethyl isocyanoacetate under mild conditions, which provides rapid synthetic access to 67 (Scheme 7).(120) At present, midazolam is used for the treatment of seizures,(121) irregular sleeping patterns,(122) severe agitation, procedural sedation, and anesthesia.(123)
Scheme 7
Scheme 7. One-Pot Synthesis of Midazolam, 67, a Short Acting Benzodiazepine
Several preclinical and clinical studies have shown that blocking the calcitonin gene related peptide (CGRP) receptor could be beneficial to discover therapeutic agents for preventive treatment of migraine.(124−126) Merck Research Laboratories previously reported a potent, orally bioavailable CGRP antagonist, telcagepant (MK-0974, compound 72), for the treatment of migraines.(127,128) Further improvements in potency and PK properties of this lead compound 72 were sought via the isosteric replacement of the caprolactam core of 72 with several heterocyclic rings.(129) It was assumed that the inclusion of the heterocyclic ring in place of the caprolactam core of 72 would improve solubility and reduce plasma protein binding, resulting in lower serum shifts. Initially, one fused triazole derivative (compound 73) showed comparable CGRP antagonistic potencies in CGRP binding assay and in related cell-based functional assays to 72 (Figure 20).
Figure 20
Figure 20. Lead optimization journey of telcagepant (72) to discover 77, a potent and orally bioavailable CGRP antagonist.
Unfortunately, 73 displayed poor PK properties in rats (F = 2%), and low permeability (Papp= 4 × 10–6 cm/s) compared to 72 (rat F = 20%; Papp = 21 × 10–6 cm/s). Upon further optimization, a fused imidazole containing molecule 74 showed the highest augmentation in permeability (Papp= 24 × 10–6 cm/s) and also improved rat oral bioavailability (F = 35%). On the basis of these encouraging results, several structural analogs of 74, having different substituents at both C5 and C4 on the imidazole ring, were synthesized and tested for their in vitro CGRP antagonistic activities. Several structural analogs of 74 have shown potent CGRP antagonistic activity in the nanomolar range (structures not shown); out of them, compound 75 (Figure 20) showed improved potency compared to 74. Despite excellent CGRP antagonistic binding affinity (Ki = 0.04 nM), 75 presented poor rat oral bioavailability (F = 2%). Persistent efforts in finding potent CGRP antagonist with desirable PK properties were continued, and consequently, azaoxindole and azabenzoxazinone-containing analogs were synthesized. Among this series of analogs, compound 76 maintained good potency and showed improved bioavailability in three species, with rat (F = 33%), dog (F = 28%), and rhesus (F = 17%). But in another in vivo model, rhesus capsaicin induced dermal vasodilation (CIDV) assay; 76 unexpectedly showed lower efficacy. Moreover, unfavorable human ether-a-go-go-related gene (hERG) activity (IC50 = 3.3 μM) of 76 impeded its development. The next challenge was to overcome hERG related undesirable activity, and therefore, structural analogs of 76 were prepared by varying different oxygenated substituents on the fused imidazole ring. The synthetic approach to provide 77 containing imidazoazepane scaffold is shown in Scheme 8. Among these tested analogs, compound 77 consists of a tertiary methyl ether which displayed excellent CGRP antagonistic activity, acceptable oral bioavailability, and diminished hERG activity. Overall, this fascinating lead optimization journey of 72 has discovered the most promising compound 77 as a preclinical candidate for the treatment of acute migraine.
Scheme 8
Scheme 8. Synthetic Route for Compound 77
Very recently, a series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors were prepared and tested by Peese and co-workers at Bristol-Myers Squibb, USA.(130) The purpose of this study was to search for a potent HIV-1 integrase inhibitor that can resolve the issues for the development of resistance mutations associated with the first generation integrase inhibitors raltegravir and elvitegravir. Recently, two new integrase strand transfer inhibitors (INSTI’s), dolutegravir and bictegravir, gained FDA approval, and because of their reduced resistance mutation profile, they have been considered second generation integrase inhibitors.(131) Raltegravir, 80, was discovered by Merck Research Laboratories(132) in 2008, and BMS-707035, 81, was reported in 2018 by Bristol-Meyers Squibb as a potent HIV-1 strand transfer inhibitor.(133) By considering the binding patterns of 80 and 81 into the integrase enzyme, Bristol-Meyers Squibb researchers decided to replace the amide within the pyrimidinedione chemotype (as present in 80 and 81) with different bioisosteres to improve activity against first-generation-resistant mutants while maintaining activity against wild-type integrase. New synthesized azole heterocyclic derivatives were initially screened for antiviral activity against the NL4–3 virus in a cellular assay. The SAR analysis revealed that oxazole, thiazole, and imidazole containing heterocycles showed potent activity against wild-type virus either equipotent or better than the parent amide, 81. However, with pyrazole, oxadiazole, and triazole, the antiviral activity was lost. These compounds were also tested for their activity toward the first-generation resistance mutations Q148R, G140S/Q148H, and N155H. The imidazole containing derivative 82 presented desirably increased potency compared with parent 81 (Figure 21). Modeling studies within the active site of the PFV (3S3N) wild-type integrase binding pocket revealed that the benzyl group of 81 is tightly positioned between Q148 and E152 (Figure 22). However, compound 82 showed a structural difference between the binding site of the wild-type integrase and the G140S/Q148H mutant. In order to provide better insights toward the altered potential of compound 82 to chelate Mg2+, bite angle (θ) and N-partial charge of the Mg2+-coordinating nitrogen were calculated and compared with 81. Overall, modeling results suggested that the wider geometry of imidazole 82 provided optimum Mg2+ binding which resulted in better steric occupancy of the mutant active site (Figure 22), and this can be correlated with the improved resistance toward G140S/Q148H.
Figure 21
Figure 21. Structures of 80, 81, and imidazole bioisostere 82, potent HIV-1 integrase inhibitors.
Figure 22
Figure 22. Binding patterns of 81 and 82 into the active sites of PFV integrase (3S3N) wild-type (A) and Q148H/G140S mutant (B). Reproduced with permission from Bioorganic &
Medicinal Chemistry Letters (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry-letters), Volume 30, 126784,
The synthetic procedure to access 82 is delineated in Scheme 9. The authors assumed that an inhibitor with a wider geometry than parent 81 would provide better binding into the active site of first-generation resistant integrase. Results of fold resistance versus wild-type (EC50mutant/EC50wt) ratio, bite angle (θ), and N-partial charge, calculated using Schrodinger Maestro Elements, revealed that 82 improved resistance coverage due to its wide geometry and optimum Mg2+ binding into the mutant active site. In rat PK studies 82 displayed low clearance (CL (L min–1 kg–1) = 10) and very low volume of distribution (Vss (L/kg) = 0.3), resulting in moderate plasma exposure. Overall, the imidazole motif was identified to be a promising amide bioisostere, and the viability of this class could be used for further structural modification to the parent pyrimidinedione series.
Scheme 9
Scheme 9. Synthetic Route To Access Imidazole Pyrimidinedione-Containing Derivative 82
Stearoyl-CoA desaturase (SCD) has two isoforms, SCD1 and SCD5, in humans. Stearoyl-CoA desaturase 1 (SCD1) plays a critical role in regulating skeletal muscle fat metabolism.(134) High SCD activity has been connected with several diseases, including diabetes, obesity, atherosclerosis, cancer, and viral infection. Therefore, inhibition of SCD1 emerged as a novel approach for the treatment of metabolic diseases, cancer, and viral infections. Shaoyi and colleagues reported thiazolylimidazolidinone-based SCD1 inhibitors and evaluated their potential for treating metabolic diseases.(135) Initially, the Xenon group identified 2-aminothiazole-based SCD1 inhibitor 85 with moderate activity (mouse SCD1; IC50 = 3400 nM), and structural modification of 85 identified the more potent SCD1 inhibitor 86 with an IC50 (mouse) of 512 nM. Unfortunately, compound 86 showed poor human SCD1 activity determined by human liver cancer (HepG2) cell assay (IC50 = 2677 nM), and it was assumed that amide moieties at the C2- and C4-position of the thiazole core are the potential contributors for its poor permeability or stability in HepG2 cells. In order to improve selectivity and metabolic stability, as well as PK properties, the replacement of the amide bond at the C2-position in compound 86 (Figure 23) was undertaken by introduction of different five- or six-membered heterocycles.
Figure 23
Figure 23. Bioisosteric replacement of the amide functional group in the identification of potent SCD1 inhibitors.
From this series of analogs, compound 87, an imidazolidinone-containing bioisostere, was identified as the most potent inhibitor in both the mouse SCD1 assay (IC50 = 28 nM) and the HepG2 SCD1 (IC50 = 53 nM) assay, but its metabolic stability was poor (10% remaining after 30 min incubation with 0.5 mg/mL rat liver microsomes). To overcome this, SAR studies continued with the thiazolylimidazolidinone (87) as the center core structure and variation of substituents on both the left (R1) and right (R2) side in the new analogs.
A new SAR was derived from these analogs that showed homologation at R1 by just one carbon led to drastically decreased SCD1 activity. In contrast, on the right side, a longer chain length up to propyl was able to maintain the SCD1 inhibitory activity. As illustrated in Scheme 10, imidazolidinone bioisostere was prepared by reacting ethyl 2-amino-4-methylthiazole-5-carboxylate (89) with 2-chlororethyl isocyanate followed by in situ cyclization in the presence of potassium carbonate. Next, further alkylation of 90 with 4-fluorobenzyl bromide afforded the substituted imidazolidinone moiety (88). Compound 88 (R1= pyridine-3-ylmethyl; R2 = 4-fluorobenzyl) resulted in the most potent SCD1 (mouse SCD1 IC50 = 6 nM; HepG2 SCD1 IC50 = 10 nM) activity along with acceptable rat liver microsomal stability (67% remaining after 30 min incubation with 0.5 mg/mL rat liver microsomes). However, in the resultant clinical studies of 88, adverse effects related to SCD1 inhibition were observed that impeded further development.
Scheme 10
Scheme 10. Synthetic Route for Compound 88
D. Tetrazole
The tetrazole ring is frequently used as a metabolism-resistance bioisosteric replacement for carboxylic acids.(18,136) However, several authors have also examined the capability of a tetrazole ring as an amide bioisostere, and subsequently, tetrazole gained attention due to its viability for amide bond replacement. In a first example from the protein arginine deiminases (PADs) inhibitor field, tetrazole Cl-amidine analogs were identified as potent PAD inhibitors that show better antiproliferative activities in U2OS (PAD-4 expressing osteosarcoma bone marrow) cells as compared to the parent 92, Cl-amidine (Figure 24).(137)
Figure 24
Figure 24. Structure of 92 and its bioisostere 93, potent PAD inhibitors.
Human proteins undergo a range of post-translational modifications (PTMs) such as citrullination which is catalyzed by PADs, involving the hydrolysis of arginine residues to form citrulline. Abnormal PAD activity is linked with onset and progression of ulcerative colitis, inflammatory bowel disease, rheumatoid arthritis, lupus, and certain cancers.(138) Compound 92 belongs to the haloacetamidine class that showed efficacy in a variety of preclinical models of autoimmune diseases and cancer. As 92 is a peptide-based compound; it primarily suffers from metabolic degradation by proteolysis. In this context, structural modifications of the parent compound (92) by replacing the C-terminal amide bond with a tetrazole ring to improve potency, selectivity, and bioavailability were performed. Tetrazole analogs of compound 92 were initially screened for their potency and selectivity by determining kinact/KI values (a measure of potency for an irreversible inhibitor) for PAD1, -2, -3, and -4. Compound 93, a biphenyl tetrazole tert-butyl Cl-amidine (the synthetic route of 93 is given in Scheme 11), showed the best potency among all tested analogs and therefore was evaluated in an antiproliferative activity assay using U2OS cells at the fixed concentration of 20 μM. Results displayed that 93 (EC50 = 10 ± 2.5 μM) has 16-fold better activity than the parent 92 (EC50 = 160 ± 20 μM), which could be attributed to its increased hydrophobicity that enhanced cell penetration.
Scheme 11
Scheme 11. Synthetic Route To Access the Biphenyl Tetrazole tert-Butyl Cl-amidine-Containing PAD Inhibitor 93
Previously it was shown that PAD-4 isozyme-mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap (NET) which causes direct organ damage and can trigger endothelial as well as epithelial cell death.(139) Therefore, in this case, inhibiting PAD-4 would be helpful to reduce NET formation. Compound 92 has been shown to block NET formation and modulate the lupus phenotype in animal models.(140) Although compound 93 had very poor in vitro inhibitory values against the PAD-4 isozyme compared to parent 92, it was checked for its potential to block NET formation by using a DNA/neutrophil elastase overlap assay. Strikingly, 93 was significantly more potent than 92 in the NET assay, possibly due to its hydrophobic nature, which enhanced cellular uptake.
A similarly successful tactic has been described for the identification of potent neuroprotective agents in a series of 1,2-dithiolane-based analogs. Many studies reported that LA is a potent antioxidant and it can regenerate intracellular glutathione (GSH), vitamin C, and vitamin E levels.(141,142) Also, it has beneficial effects in a number of pathological conditions such as inflammation, neurodegeneration, ischemia–reperfusion injury, diabetes, etc. related to oxidative stress.(143) Koufaki and co-workers designed a small library of LA (or 1,2-dithiolane) based analogs where the amide bond present in LA amide-dopamine conjugate (96) was bioisosterically replaced by several heterocyclic five-membered rings including triazole, oxadiazole, tetrazole, and thiazole to improve neuroprotective activity with that of parent 96.(144) The authors did not comment on why they decided to make conformational changes from the natural trans-amide (96) to the cis-amide-like tetrazole (97). Results of in vitro neuroprotection assay using glutamate challenged HT22 cells revealed that the tetrazole containing analog (97) displayed the strongest neuroprotective activity compared to the parent 96 and also among all tested compounds (Figure 25).
Figure 25
Figure 25. Structures of LA amide–dopamine conjugate 96 and its tetrazole containing bioisostere 97.
The synthetic route to access 97 is delineated in Scheme 12, i, in which trimethylsilyl azide (TMSA) in the presence of triphenylphosphine and diisopropyl azodicarboxylate (DIAD) was used to obtain the desired tetrazole intermediate. The primary SAR analysis on this series of compounds showed that potent neuroprotective activity could be achieved by insertion of the heteroaromatic head in the alkyl-1,2-dithiolane chemotype in conjunction with other antioxidant moieties such as the catechol.
Scheme 12
Scheme 12. General Synthetic Route To Access Tetrazole, Nonclassical Amide Bioisostere
In 2009, Koufaki and co-workers again conducted a similar type of study in which novel 1,2-dithiolane/chroman hybrids were designed and evaluated for their neuroprotective potential in glutamate-challenged HT22 cells.(73) Several nonclassical bioisosteres such as triazole (discussed in the triazole section, 29), oxadiazole (discussed in the oxadiazole section, 40), and tetrazole were employed to replace the amide bond in the parent compound 28. Here, we highlight the in vitro neuroprotection assay results obtained upon tetrazole installation in compound 100 (Figure 26). This compound was synthesized according to the general synthetic procedure depicted in Scheme 12, i. In this study, the authors did not discuss effects on activity related to the restricted conformation obtained with the cis-amide-like tetrazole (100) compared with the trans-amide (28). Being less flexible in comparison with other dithiolane/chroman hybrids of the same series, 100 exhibited a slight reduction in activity (EC50 = 3.04 ± 1.15 μM) compared to the parent amide 28 (EC50 = 2.10 ± 0.40 μM). However, the percentage efficacy of both 100 (100%) and 28 (95%) was almost equal, which signifies its potent neuroprotective ability.
Figure 26
Figure 26. Molecular structures of parent LA-amide analog 28 and its tetrazole bioisostere 100.
Neuronal nicotinic acetylcholine receptors (nAChRs) belong to the “Cys-loop” superfamily of ligand-gated ion channels, widely expressed throughout the brain, and are suggested to be a potential therapeutic target for the treatment of cognitive disorders.(145,146) Several studies also indicate that α7-AChRs share a target for therapeutic intervention in AD and schizophrenia.(147,148) In an effort to identify more potent α7-AChRs agonist with desirable drug-like properties, Beinat and colleagues(149) explored the SAR of SEN12333 (101), a potent α7-AChR agonist (Ki = 670 ± 119 nM) developed by another group at Siena Biotech and Wyeth (Figure 27).(150) Due to limited SAR studies for this chemotype (101), these authors have previously identified that the four-carbon chain linker is essential for optimal binding and functional activity at α7-AChRs.(151) In the present work, the authors investigated the role of the amide bond in 101, particularly its connectivity and bioisosteric replacement (Figure 27).
Figure 27
Figure 27. Amide bond bioisosteric modification in 101 with a tetrazole functionality (102).
Several compounds were synthesized and tested for their agonistic activity for α7-AChRs. The transposition of amide 101 to the reverse amide (structure not shown here) resulted in a marked decrease of affinity at α7-AChRs over that of 101. The bioisosteric replacement of the amide in 101 with a tetrazole ring (a cis amide isostere) was undertaken to provide further mechanistic details into the binding mode of 101 at α7-AChR and potentially reduce the number of rotatable bonds within the molecule. X-ray crystallographic studies were performed to identify the solid-state conformations for both 101 and a tetrazole containing bioisostere (102). Compound 102 was readily synthesized from a corresponding amide using phosphorus pentachloride to initially afford the respective imidoyl chloride derivative followed by the addition of trimethylsilylazide to furnish the tetrazole moiety (Scheme 12, ii). The obtained Oak Ridge thermal ellipsoid plots (ORTEPs) of 101 and 102 are shown in Figure 28. These plots revealed that amide (101) adopts a trans-conformation at the lowest energy. However, the tetrazole ring (102) locks the amide bond into cis-conformation and resides in a bent form. If the binding conformation of 101 is similar to the low energy (i.e., trans-conformation), these studies suggest the binding mode of 101 and 102 would be vastly different. Contrary to expectations of the tetrazole bioisostere (102), affinity to α7-AChR was completely abolished (Figure 27), which may be due to increased steric hindrance or electronics of the tetrazole ring at the receptor-binding site. Thus, the obtained SAR results provided valuable insights about the essential molecular requirements of this particular chemotype and concluded that the original amide bond connectivity, as in 101, is favorable for binding affinity as well as agonistic activity at α7-AChRs.
Figure 28
Figure 28. Oak Ridge thermal ellipsoid plots of 101 (A) and 102 (B). Reproduced with permission from European Journal
of Medicinal Chemistry (https://www.sciencedirect.com/journal/european-journal-of-medicinal-chemistry), Volume 84, pp 200–205,
E. Pyrazole
Prolylcarboxypeptidase (PrCP) or prolinecarboxypeptidase represents a potential therapeutic target for the treatment of cardiovascular, inflammatory, and metabolic diseases, wherein substantial efforts have been made to generate potent PrCP inhibitors.(152−154) A medicinal chemistry campaign to discover novel inhibitors of PrCP at Merck Research Laboratories investigated the use of a pyrazole scaffold as an amide bioisostere in a class of previously reported PrCP inhibitors 103 and 104 to modify their PK properties while maintaining potency for both human (h) and mouse (m) PrCPs.(155) Compounds 103 and 104 showed potent PrCP in vitro inhibitory activity of IC50 (h, m) = 3.5 and 5 nM and IC50 (h, m) = 2.5 and 1.4 nM, respectively (Figure 29). In mouse PK studies, 104 showed a long half-life, which results in improved oral bioavailability as compared to 103, which suggested that the morpholine substituent replacement could be afforded without disturbing potency. Next, when the pyrazole ring was installed (compound 105) in place of the amide function on this chemotype, it brought a significant loss in PrCP inhibitory activity. Further optimization was made to regain the potency. In due course, compound 106 was identified as the most potent PrCP inhibitor containing a pyrazole bioisostere (Figure 29).
Figure 29
Figure 29. Bioisosteric replacement of amide (103 and 104) with pyrazole (105 and 106) to discover potent PrCP inhibitors.
Moreover, this compound also showed a modest half-life and oral bioavailability in the mouse comparable to the original amides, i.e., 103 and 104. In summary, the preliminary installation of the pyrazole (105) as an amide surrogate attenuated the in vitro PrCP potency; however, an exhaustive SAR analysis showed that the exchange of an aminocyclohexane core with a piperidine motif was beneficial in restoring the in vitro PrCP activity. Moreover, simplified analogs with no stereogenic centers including 106 were also potent PrCP inhibitors.(156)
F. Miscellaneous Heterocyclic Amide Bioisosteres
Several studies have shown that the CB1 receptor, a member of the G-protein-coupled receptor (GPCRs) family, is a promising therapeutic target against a wide range of pathological conditions including mood and anxiety disorders, neuropathic pain, Huntington’s disease (HD), PD, multiple sclerosis, traumatic brain and spinal cord injury, glaucoma, obesity, myocardial infarction, stroke, and hypertension.(157,158) Previously, the indole-3-carboxamide derivatives 107 and 108 were reported as CB1 agonists which showed potent antinociceptive activity in the mouse tail-flick test after intravenous (iv) administration, and both demonstrated a fast onset and short duration of action.(159,160) Efforts were made at improving metabolic stability through a bioisosteric approach, and thus, introduction of conformationally constrained and steric blocking groups in place of the piperazine amide (107 and 108) was evaluated (Figure 30).(161)
Figure 30
Figure 30. Amide versus thiadiazole bioisosterism in search of potent CB1 agonist.
New compounds consisting of different bioisosteric heterocycles (oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, thiazole, and thiadiazole) with a simple tertiary amine were synthesized and evaluated for in vitro CB1 agonist activity by using Chinese hamster ovary (CHO) cells doubly transfected with human CB1 and luciferase. The SAR analysis of this series revealed that all new compounds retained CB1 agonistic activity. However, the replacement of the piperazine amide by a 1,2,4-thiadiazole motif (109) provided the best combination to retain CB1 agonist potency (pEC50 = 7.7) and metabolic stability [MLM = 71; human liver microsome (HLM) = 89] within the series (Figure 30).
Next, SAR was explored around the amine moiety and several compounds were prepared and evaluated for CB1 receptor agonistic activity and metabolic stability. These compounds showed CB1 agonistic activities comparable with 109. Success was achieved upon constraining the diethyl fragment into a pyrrolidine ring (compound 110) and with compound 111 containing a similar sized ethyl group in place of the 7-methoxy group (Figure 30). This compound displayed comparable potency and stability to 110 and was therefore selected for advanced in vitro experiments. Results demonstrated that 111 showed high binding affinities for both human CB1 (pKi = 8.2) and CB2 (pKi = 8.5), tested by radioligand competition binding assay using [3H] CP 55940 binding to either human CB1 or CB2 receptors expressed in insect Sf9 membranes. Figure 31 shows the superimposed images of 111 and 107 suggesting appropriate biomimicry by the thiadiazole moiety. Moreover, in the mouse tail-flick test, a preclinical model of nociception, 111 showed improved duration of action after iv administration compared to the parent 107.(161)
Figure 31
Figure 31. Superimposition modeling image of 107 (green) and 111 (orange). Reproduced with permission from Bioorganic &
Medicinal Chemistry Letters (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry-letters), Volume 21, pp 506–509,
The matrix metalloproteinases (MMPs), also called matrixins, belong to the metzincin group of proteases, which possess a conserved zinc-binding motif in their catalytic site. These MMPs play a crucial role in many physiological processes, and their expression is increased in various pathological conditions such as inflammation, angiogenesis, metabolic bone disease, and cancer. Therefore, inhibitors of MMPs are valuable compounds for therapeutic development in these diseases.(162−164) A series of succinyl hydroxamate matrix metalloproteinase inhibitors were prepared by incorporating both aromatic and aliphatic substituents in place of an amide moiety present in general structure 112 (Figure 32).(165)
Figure 32
Figure 32. General structure (112) showing the molecular template for designing MMP inhibitors, isosteric replacement of the C-terminal amide bond in 113 with 3-acyl indole (114), and the structure of marimastat, (115), a broad-spectrum MMP inhibitor.
Previously, the 3-acyl indole ring had been employed as an isosteric replacement for an aryl amide moiety in developing platelet-activating factor (PAF) antagonists. This modification enhanced the binding energy of the series and stabilized a hydrolysis-prone amide function which resulted in the identification of several PAF antagonists with good oral bioavailability.(166) In this study, the authors replicated this strategy and replaced the C-terminal amide (113) with 3-acyl indole (114) to ascertain its effects on MMP inhibitory potency and oral bioavailability. Results were encouraging, and as expected, 114 was found to be a potent broad-spectrum MMP inhibitor (Figure 32). The synthetic route for 114 is delineated in Scheme 13. This compound showed modest oral bioavailability in rats similar to 113. Furthermore, in monkeys, 114 at an oral dose of 10 mg/kg exhibited a half-life of 20 h, which was comparable to marimastat (115) (oral dose, 10 mg/kg; 27 h), a broad-spectrum MMP inhibitor taken as reference (Figure 32).
Scheme 13
Scheme 13. Synthesis of Indole Bioisostere 114, a Potent MMP Inhibitor
An example where an acetamide functional group was replaced with a trifluoroethyl, pyridine, pyrimidine, pyrazine, or thiazole ring was reported in the optimization of antagonists of the adenosine A2A (A2A) receptor, a GPCR mediating the physiological actions of adenosine, involved in coordinating motor functions.(167−169) Previously, the authors have reported a series of 2,4,6-trisubstituted pyrimidines that showed potent antagonism at the A2A receptor and confirmed their efficacy in haloperidol-induced catalepsy. The molecular structures of all these compounds possess an acetamide group, due to which they showed varied stability under acidic conditions; therefore, this acetamido fragment was bioisosterically replaced from compound 119 (a preclinical candidate), chosen as the starting point (Figure 33).
Figure 33
Figure 33. Molecular structures of the parent amide 119 and pyrazine (120), thiazole (121), and pyridine (122) bioisosteres.
Preladenant was selected as the standard reference compound in vitro human A2A receptor binding assays.(170) Merck introduced preladenant (SCH 420814) as a potent A2A receptor antagonist for the treatment of PD. Results from clinical trials suggested the discontinuation of preladenant due to adverse events.(169,171) The preliminary SAR analysis showed that the installation of pyrazine with 1,2,3,4-tetrahydroisoquinoline (compound 120) improved potency more than 10-fold compared to the parent 119. It exhibits superior antagonistic potency of 1.1 nM at human A2A receptor comparable to that of preladenant (1 nM). The synthetic route to obtain the pyrazine bioisostere 120 is given in Scheme 14. On the other hand, two more compounds consisting of a thiazole with (R)-2-(methoxymethyl)pyrrolidine (121) and a pyridine with pyrazole (122) also displayed superior potency compared to parent 119 (Figure 33). Thus, the observed SAR trend on this series was unclear, warranting further detailed investigations.
Scheme 14
Scheme 14. Synthetic Route for Obtaining the Pyrazine Bioisostere 120, a Potent A2A Receptor Antagonist
Tyrosine kinase 2 (TYK2) belongs to the Janus kinase (JAK) family and plays a critical role in driving interleukin 12 (IL-12) and interleukin 23 (IL-23) pathways, and these pathways are correlated with the pathogenesis of autoimmune diseases such as psoriasis, lupus, multiple sclerosis, and inflammatory bowel disease.(172) Therefore, TYK2 appeared as a therapeutic target for various human autoimmune diseases. The challenging task is to develop a selective TYK2 inhibitor over other JAK family members (i.e., JAK1, -2, -3) because of their high sequence homology to TYK2.(173) Lead 125 was identified as a TYK-2 inhibitor, and its subsequent optimization to a fluorocyclopropane analog 126 was reported. To improve TYK2 potency, the authors prepared several structurally constrained analogs derived from lead 126, where the amide bond was cyclized onto the pyridine ring to form fused heterocycles (Figure 34).(174) The prepared analogs were evaluated for their TYR2 and JAK2 inhibition and resulted in some active scaffolds including imidazopyridine, oxazolopyridine, thiazolopyridine, and pyrazolopyridine. Among them, the imidazopyridine containing analog, 127, showed an IC50 value of 1.7 nM for TYR2 along with increased selectivity over JAK-2 compared to parent 125.
Figure 34
Figure 34. Structures of lead TYR2 inhibitor 125 and its optimized analogs 126–128.
These results show that the constrained core (127) is a better choice over the unconstrained amide core (125) in terms of improving the selectivity for JAK2. Further optimization of 127 by replacement of the cyclopropylamide portion with an aminopyrimidine moiety and appending a cyano group was performed. Earlier, it was observed, as in the case of unconstrained amide series (126), that the introduction of a cyano group at the fourth position of the dichlorophenyl ring led to significant improvement in in vivo clearance in rodents. Of these new analogs, compound 128 bearing a 6-methylpyrimidine showed potent inhibition of TYK2 (Ki = 0.7 nM) and the IL-23 pathways in cells (EC50 = 66 nM) along with high selectivity over JAK2. As described in Scheme 15, compound 128 was synthesized by reacting 2,6-dichloro-4-iodobenzoic acid (129), 2-chloropyridine-3,4-diamine, and polyphosphoric acid. The resulting isolated product was treated with POBr3 solution to give the desired compound 130 (4-bromo-2-(2,6-dichloro-4-iodophenyl)-3H-imidazo[4,5-c]pyridine). Next, the mixture of compound 130, Zn(CN)2, and Pd(PPh3)4 was heated to obtain compound 131. Finally, microwave-assisted Pd-catalyzed coupling reaction of compound 131 and 6-methylpyrimidine-4-amine was done to obtain 128. This compound demonstrated high permeability and exhibited moderate stability in liver microsomes. Moreover, in mice, 128 displayed a dose-dependent reduction of interleukin 17 (IL-17) production in a PK/PD model and in an imiquimod-induced psoriasis model.(174)
Scheme 15
Scheme 15. Synthetic Route To Obtain Compound 128, a Potent TYR2 Inhibitor
During research to identify new dopamine D2 receptor modulating agents, Baures and co-workers demonstrated the bioisosteric relationship existing between the amide bond (l-prolyl-l-leucylglycinamide 132) and diketopiperazine (DKP) functionalities (133, 134, and 135) (Figure 35).(175) Earlier, these authors have reported that 132 modulates the dopamine D2 receptor by increasing the affinity of the receptor for agonists.(176,177) Compound 133 was designed previously(178) to mimic an N-terminal “C5” conformation involving an intermolecular hydrogen bond between the prolyl nitrogen and the lactam NH in an analog of parent 132 (structure not shown), which possessed better activity in a number of pharmacological assays.(179,180) In order to further explore SAR, the DKP containing compounds 134 and 135 were designed in which a “C5” conformational mimic was incorporated into the parent structure (132) and a bicyclic lactam moiety was assimilated (present in a potent 132 analog, structure not shown), respectively.(181) The dopamine receptor modulation ability of 134 and 135 was assessed by measuring activity in a [3H]spiro-peridol/N-propylnorapomorphine (NPA) D2 receptor competitive binding assay in the presence as well as absence of 5′-guanylyl imidodiphosphate (Gpp(NH)p); KH and KL represent the inhibitor constant (Ki) of agonist calculated for the high- and low-affinity components of the [3H]spiroperidol binding, respectively (Figure 35).
Figure 35
Figure 35. Bioisosteric replacement of the amide within 132, with diketopiperazine (133, 134, and 135), to develop potent dopamine D2 receptor modulators.
The obtained results suggested that both 134 and 135 increased the affinity of the dopamine receptor for agonists and the percentage of dopamine D2 receptors which existed in the high-affinity state. However, the potency seen with 134 and 135 was greater than the parent 132, whereas it was not as great as observed for 133. Furthermore, compound 134 was found to be 10 times more potent than 135 which in turn was 10 times more potent than the parent 132 in an in vivo assay measuring apomorphine-induced rotational behavior in a 6-hydroxydopamine-lesioned rat model of PD. The synthesis of a diketopiperazine scaffold was accomplished by reacting N-chloroacetyl derivative (136) with l-leucine benzyl ester to obtain 137, which further gave compound 134 over several steps (Scheme 16). Many authors have also shown the bioisosteric relationship between amide and DKP which has resulted in the identification of a number of peptidomimetics and β-turn mimetics.(182)
Scheme 16
Scheme 16. Diketopiperazine Bioisostere Synthesis from l-Proline To Obtain Compound 134
Retroinverted and Reverse Amides as Amide Bioisosteres
ARTICLE SECTIONS
The retroinverted or retroinverso alteration (NH–C(O)) is a popular approach for improving the resistance of an amide-containing molecule toward enzymatic cleavage, wherein the amide bond geometry and topology are maintained. This modification can be achieved by retroinversion from N → C to C → N, which does not alter the conformational flexibility of the molecule but improves the in vivo stability and prevents amide bond hydrolysis by proteases. On the other hand, a reverse amide, also known as a retro-amide (−C(O)NH−), retains the hydrogen bonding properties of an amide but is diametrically opposed.(11) Several lines of experimental evidence suggest that the change in the location of the hydrogen bond donor and acceptor influences bioactivity.(149,183,184) Here, examples where the use of a retroinverted or reverse amide produced beneficial as well as detrimental effects are discussed.
An interesting example where the installation of the retroinverted amide as an amide isostere significantly affected target specificity is a novel aldo–keto reductase 1C3 (AKR1C3) inhibitor for the potential treatment of acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL).(183,185−187) Several structural chemical classes, such as steroids, flavones, jasmonates, and nonsteroidal anti-inflammatory drugs (NSAIDs), have been tested to identify and develop potent AKR1C3 inhibitors.(183) Unfortunately, the lack of inhibitory potency and isoform selectivity had no observable clinical efficacy in castration-resistant prostate cancer (CRPC) patients,(188−190) preventing further clinical development. It has been reported that baccharin, a natural product isolated from honeybee propolis, is a highly selective inhibitor (500-fold selectivity over AKR1C2) of AKR1C3, with an IC50 value of 0.11 μM.(191) This discovery has made baccharin a promising hit compound for the development of more potent and selective AKR1C3 inhibitors. Similarly, we previously reported the preliminary SAR of several baccharin analogs as AKR1C3 inhibitors.(192) In another study, we reported the design, synthesis, and evaluation of potent AKR1C3 inhibitors containing a more stable amide bioisostere. However, their selectivity over AKR1C1 and AKR1C2 isoforms was relatively low.(193)
A recent report describes a library of compounds that were designed utilizing the concept of bioisosterism to obtain an extensive SAR map for AKR1C3 inhibition based on a baccharin pharmacophore.(183) The results of in vitro enzyme inhibition assays indicated that several compounds produced a marked inhibition of AKR1C3 and had moderate to significant isoform selectivity for AKR1C3 over the other isoforms. Compound 138, a meta-amide baccharin analog, had potent AKR1C3 inhibition (AKR1C3 IC50 = 0.066 μM), with a 109-fold selectivity for AKR1C3 (Figure 36). Alteration of the central ring substitution pattern to an all meta arrangement and installation of a retroamide bioisostere yielded compound 139, which was equipotent with 138 (AKR1C3 IC50 = 0.07 μM). Most importantly, this compound had >2800-fold selectivity for C3 over C1 and C2, thus making it the most selective AKR1C3 inhibitor across all known classes of inhibitors reported thus far (Figure 36). Modeling experiments confirmed that 139 showed better binding affinity through the formation of strong hydrogen bonds to the carbonyl of the retroinverted amide, due to the reduced distance between the amino acid hydrogen bond donors and the amide carbonyl acceptor (Figure 37).
Figure 36
Figure 36. Structures of an amide-containing baccharin analog 138, a potent but low selective AKR1C3 inhibitor, and 139, a potent and highly selective retroinverted amide bioisostere.
Figure 37
Figure 37. Compound 139 docked within the active site of AKR1C3 (gray, PDB code 3UG8): strong predicted hydrogen bond (green dotted line) and weak predicted hydrogen bond (white dotted line). Reproduced with permission from Journal of Medicinal Chemistry,(183) Copyright 2019 American Chemical Society.
Compound 139 was synthesized in several synthetic steps, starting from 3-bromo-5-iodobenzoyl chloride (Scheme 17). The combination of compound 139 and the antileukemic drugs daunorubicin and cytarabine produced synergism against AML and patient derived T-ALL cells. Furthermore, 139 had a >100-fold dose reduction index in a daunorubicin-resistant AML cell line and >100-fold dose reduction of cytarabine in both AML cell lines and primary T-ALL cells.
Scheme 17
Scheme 17. Synthetic Route To Access the Potent and Highly Selective AKR1C3 Inhibitor 139
In the search for a potent melatonergic receptor agonist, a series of melatonin-based compounds has been described by de la Fuente Revenga and co-workers, where the acetamido group of melatonin (143) was replaced with several amide bioisosteres such as a reversed amide, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,3,4-oxadiazol(thio)ones, 1,3,4-triazol(thio)ones, and 1,3,4-thiadiazole.(184) Compound 143, N-acetyl-5-methoxytryptamine, is a neurohormone secreted primarily by the pineal gland during the night.(194) The physiological and pharmacological effects of 143 are primarily mediated by the activation of the high-affinity GPCRs, melatonin receptor 1 (MT1R) and melatonin receptor 2 (MT2R).(195) Numerous studies have shown that 143 and its ligands have the potential to treat pathological conditions such as sleep disturbances, type 2 diabetes, obesity, major depression, mood disorders, neurodegeneration, severe pain, inflammation, and certain forms of cancer.(196−198) Earlier attempts involving detailed SAR exploration indicated that modifications on the acetamido group of 143 were detrimental as they caused either a substantial decrease or complete loss of binding affinity and potency for melatonin receptors (MTRs).(199−203) Furthermore, in silico studies indicated that the acetamido group of 143 can form captodative hydrogen bonds at the binding site of MTRs.(204) Therefore, the authors installed different amide bioisosteres to replace the N-acetyl fragment in 143 in order to ascertain the structural binding pocket of this fragment in terms of its size, shape, electronic distribution, and lipophilicity. The binding and functional activity studies of the prepared compounds were determined using human MT1R or MT2R stably transfected in the Chinese hamster ovary cells. The results indicated that the replacement of the acetamido group of the parent 143 by retroamides (144 and 145) produced the highest binding affinities, with Ki values in the low nanomolar and subnanomolar range (Figure 38).
Figure 38
Figure 38. Structures of the parent amide 143 and the reverse amide bioisosteres 144 and 145, MTR ligands.
The SAR analysis of retroamides with unsaturated side chains indicated that alkenyl or alkynyl substitution was well tolerated but the length of the spacer affected the potency of the compounds. For example, retroamides with one methylene unit (structures not shown here) did not produce favorable results. In contrast, both 144 and 145, which had an ethylene spacer, retained potency at MTRs. The synthetic route to access 144 and 145 is delineated in Scheme 18 where commercially available 2-(5-methoxy-1H-indol-3-yl)alkanoic acid was activated with carbonyldiimidazole (CDI) and then reacted with propargylamine or allylamine to obtain 144 and 145, respectively. Furthermore, compound 144 was analyzed for brain repairing efficacy, i.e., neurogenic potential, by using rat neural stem cells as an in vitro system. The results of this experiment indicated that 144 induces moderate cell differentiation but failed to stimulate neural maturation. Overall, the bioisosteric replacement of an amide with a retroamide yielded compounds that retained MTRs binding affinity, suggesting that the acetamido group could be transformed without a significant loss of binding affinity.(184)
Scheme 18
Scheme 18. Synthetic Preparation of the Melatonin-Based Compounds 144 and 145
The above examples illustrate that despite their relatively simple structural differences, reverse amide bioisosteres can overcome issues related to the potency and selectivity of amide-containing counterparts. There are of course many examples where reverse amide surrogation does not produce beneficial pharmacological effects, and one such case is discussed in the tetrazole section of this review above, where Beinat and colleagues installed reverse amide and tetrazole isosteres to develop potent α7-AChRs agonists.(149)
Urea Bioisosteres
ARTICLE SECTIONS
Urea has the ability to form multiple stable hydrogen bonds with a variety of protein and receptor targets, a very important element for its molecular recognition and bioactivity. The central carbonyl functions as a nucleophile and hydrogen bond acceptor with the ability to accept two hydrogen bonds. The protons on the two nitrogens serve as hydrogen bond donors, capable of providing two to four hydrogen bonds dependent on substitution.(205) These interactions allow for specificity in drug action, biological activity, and manipulation of physicochemical properties, which is why urea derivatives are widely used in medicinal chemistry. Ghosh and co-workers proposed that substitution on the urea nitrogen atoms significantly affects the conformational preferences of urea derivatives due to the delocalization of nonbonded electrons α to the carbonyl atom.(206) Urea is hydrotropic, meaning it can be used to promote the solubility of poorly soluble drugs and improve the permeability of molecules it is introduced into.(205) In some cases, urea compounds can have poor solubility or permeability. However, various techniques can be used to address this issue, for instance, modulating the hydrogen bonding ability of ureas by introducing electron donating or electron withdrawing groups (EWGs) on the substituents, disruption of molecular planarity to enhance solubility by introducing substituents on one urea nitrogen to make it nonsymmetrical and break planarity, or introducing a substituent at the ortho position of N-aryl groups of arylureas.(206) Overall, solubility and permeability depend on other substitutions within the molecule. There are several FDA approved drugs containing the urea moiety for use in a variety of human diseases such as antidiabetics, antibacterials, anticancer, and other therapeutic agents. Urea derivatives play a vital role in the regulation of various pharmacological activities such as the ability to improve potency and target selectivity, modulation of physiochemical properties, and contribution to metabolic liability.(205)
In order to identify the necessary structural motifs for potent acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibition in vitro and hypocholesterolemic agents in vivo, Roark and colleagues employed a peptidomimetic approach. Initially, a series of oleic and fatty acid analogs were synthesized wherein the peptide amide bonds in N-(2,4,6-trimethoxyphenyl)- and N-(2,6-dimethylphenyl)oleamides, and stearamides underwent various bioisosteric replacements to examine effect on biological activity. Results showed that only two urea bioisosteres 148 and 149 (Figure 39) retained considerable inhibitory activity in vitro (IC50 = 0.32 μM and 0.16 μM, respectively). Although 149 showed a 4-fold decrease in potency in vitro (IC50 = 0.16 μM) compared to its amide counterpart 147 (IC50 = 0.043 μM) (Figure 39), it was more potent in vivo. When 149 was dosed at 0.05% in the diet of cholesterol-fed rats, it lowered total cholesterol by 55% versus a 38% decrease in total cholesterol with the amide-based compound at the same dose. As a result, only bioisosteres having both hydrogen bond donor and acceptor functionalities yielded compounds that retained ACAT inhibitory potency activity in vitro as shown by sulfonamide, thioamide, retroamides, urea, carbamate, and thiocarbamate bioisosteres. Additionally, the location of the hydrogen bond donor and acceptor was crucial as retroinverted amides were less potent than the amides. Bioisosteric analogs with no, or one, hydrogen bond donor or acceptor functionality, as shown by ester, oxymethylene, thiomethylene, methyleneamino, sulfoxide, ketomethylene, and hydroxyethylene, led to uniformly inactive compounds. Therefore, the urea moiety was an acceptable bioisosteric replacement for the amide.(207) Later the same group extended this original fatty acid amide series to encompass β-ketoamides.(208) A simple series of N,N′-diphenylurea derivatives were also found to be potent ACAT inhibitors.(209) Further evaluation led to the identification of a novel series of potent urea derivatives and a new ACAT inhibitors. Structure–activity relationship studies in this series revealed that a certain spatial arrangement, five atom spacer, between two phenyl rings is critical, lipophilic bulk is well tolerated, the 2,6-positions of the 2,6-diisopropylphenyl are essential to orient the required carbonyl group out of plane of the phenyl ring in order to obtain optimal enzyme interactions. Isosteric replacement of the urea moiety resulted in significantly less active compounds (10- to 1000-fold). From this series of analogs, a potent inhibitor of ACAT (IC50 = 0.017 μM) (150) (Figure 39) was discovered; it dose-dependently lowered plasma cholesterol in cholesterol-fed rats, but further investigations showed the compound was poorly absorbed. To overcome this, SAR studies continued with N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas and compound 151 (Figure 39) was discovered (Scheme 19, i) which did not produce adrenal toxicity in guinea pigs and had substantial lipid-modulating activity in a chronic model of preestablished dyslipidemia in rats. The general synthetic route to obtain compound 151 is depicted in Scheme 19, i, where the urea moiety was furnished by reacting the corresponding isocyanate and amine. Overall, subsequent evaluation in animal models of hypercholesterolemia suggested that their physical properties were important determinants of their pharmacokinetics and efficiency.
Figure 39
Figure 39. Structures of parent amide 147, urea bioisosteres 148, 149, and 150, and 151, a potent urea ACAT inhibitor.
Scheme 19
Scheme 19. General Synthetic Route To Prepare Urea Bioisostere via Isocyanate
Bioisosteric replacement of an amide bond in (±)-15-deoxyspergualin (DSG, 155) (Figure 40), a synthetic derivative of spergualin, a product isolated from Bacillus laterosporous, was explored by Lebreton and co-workers.(210) Previously, 155 has been used as an anticancer agent and in animal transplantation either in allografts, xenografts, or graft-versus-host disease (GVHD) animal models. In 1994, 155 was commercialized in Japan as an immunosuppressive agent. However, 155 has three drawbacks limiting its use: low chemical stability in aqueous solution leading to hydroxylation, presence of the inactive (+)-155 isomer in a racemic mixture which is not reported to be immunosuppressive and can contribute to acute toxicity, and low oral bioavailability (<5%) preventing oral administration. New analogs of 155 were synthesized and tested in a GVHD model in mice. By use of a bioisosteric replacement approach, variations were implemented at the hydroxyglycine central carbon atom to prevent issues associated with chirality and hydrolytic sensitivity. Initially, a malonic derivative was identified as the first analog of a new series of potent immunosuppressive agents where the retro-inverted amide bond was linked to a hexylguanidino moiety, 156 (Figure 40). Structure–activity relationship studies where the “western-amide” was reversed compared to 155 led to active analogs at 3 and 1 mg/kg. However, other “western-amide” replacements such as a two-methylene unit, carbamate, or urea led to inactive compounds. The “eastern-amide” of the malonic derivative was varied and led to more analogs wherein a urea derivative, 157 was active at 3 mg/kg. Replacing the NH atoms of the urea by oxygen led to compound 158 which was prepared via acid–amine coupling using HOBt and DCC in dichloromethane (Scheme 20). Compound 158 was found to be very active at 3 mg/kg in a GVHD model (Figure 40). However, when compound 158 was tested in a more demanding model for acute organ rejection after heart allotransplantation, the urea derivative (157) was only slightly active, whereas compound 158 was found to be the most potent and slightly more active than compound 155 in the heart allotransplantation model in rats. This was due to the absence of chirality leading to improved chemical stability when compared to compound 158 (Figure 40); therefore, compound 158 was selected as a drug candidate.
Figure 40
Figure 40. Structures of DSG (155) and bioisosteric analogs.
Scheme 20
Scheme 20. Synthetic Procedure To Access 158, a Potent Immunosuppressor
Successful bioisosteric replacement of an amide with a urea moiety was achieved based on 1,6-naphthyridine moieties in which the lead compound 161 had similar activity as ganciclovir, an antiviral drug for human cytomegalovirus (HCMV). Previous SAR studies revealed that the optimal positions for nitrogen atoms on the naphthyridine ring are at the 1- and 6-positions.(211) Additionally, substitution at C-8 and a bulky alkoxy group at the 2′-position are beneficial for activity (Figure 41).(212) It was also discovered that the internal hydrogen bond between the NH of the amide and heteroatoms labeled N1 and O2′ (Figure 41) are key to maintaining the active conformation of the molecule. Chan and co-workers evaluated new napthyridines, wherein bioisosteric replacement of the amide group with other groups can maintain hydrogen bonds, thioamides, and urea as new anti-HCMV compounds. First, thioamide derivatives were studied due to their structural similarity to the amide motif and potential ability for in vivo stability. Results showed that methoxybenzylamine substitution was 3 times less active than the parent amide. There was only slight improvement with an increase in the bulk of alkoxy substituent to 2′-ethoxybenzylamine or 2′-isopropoxybenzylamine. Replacing the amide with a longer thioamide resulted in the loss of some desirable interaction at this position; therefore, thioamide derivatives were not further studied. Next, urea derivatives were evaluated since they have the potential to form two internal hydrogen bonds. More specifically, benzyl and phenylureas were studied due to previous SAR studies revealing that substitution on naphthyridine can enhance potency leading to substitutions at carbons 3 and 8 also being evaluated. The benzylureas revealed that unsubstituted analogs resulted in nonselective activity; the 2′ methoxy analog was active, and increasing the bulk of the substituent to isopropoxy resulted in enhanced activity. Similar results were seen in the phenylurea derivatives where an unsubstituted analog gave an inactive derivative, an alkoxy group substituent led to active compounds, and an increase in the bulk of the alkoxy group resulted in enhanced activity. The 2′ isopropoxy derivative 162 was the most active compound (Figure 41) with IC50 = 30 ng/mL in this series. Substitution on 1,6-napthyridine indicated that a cyano or methyl group at C-3 eliminated activity, whereas introducing a bromine atom at C-8 did not improve potency in urea derivatives. These novel anti-HCMV compounds revealed that ureas and amides are maintained in similar active conformation through internal hydrogen bonding. The lack of 2′-alkoxy substituents led to toxicity or no activity due to the presence of only one internal hydrogen bond and more degrees of freedom being present around the amide bond. Overall, internal hydrogen bonding is an important feature in 1,6-napthyridine urea derivatives for potent activity as HCMV inhibitors.(213)
Figure 41
Figure 41. Structures of lead compound 161 for anti-human cytomegalovirus (HCMV) and 2′-isopropoxyurea bioisostere 162.
Bioisosteric replacement of an amide with a urea moiety was compared in ceramide analogs; B13, compound 163, a ceramide analog consisting of a phenyl group instead of an alkenyl chain and (1R, 2R) configuration versus the (2S, 3R) configuration of natural ceramides, was synthesized.(214) Previously, 163 was shown to have potent cytotoxic activity in human colon cancer cells that underwent apoptosis.(215) It also displayed selective toxicity toward malignant cells over nonmalignant cells. Moreover, it prevented metastasis in liver colon cancer cells of a nude mouse model. This led to the synthesis and evaluation of 3-alkyl-1-(1-methyl-2-phenylethyl)ureas, novel analogs of 163.(216) The amide group of 163 underwent a bioisosteric replacement with urea in the presence or absence of a p-nitro group on the phenyl ring, two hydroxyl groups on the backbone, varying stereochemistry on the backbone along with varying chain length of the alkyl chain with octyl and dodecyl groups. These derivatives were evaluated for their cytotoxic activity in five human tumor cell lines (Caki-2, human renal cancer; HT-29, human colon cancer; A549, human lung cancer; PC-3, human prostate cancer; HL-60, human leukemia). Thus, compound 163, displayed modest activity in the HL-60 cell line (IC50 = 28 μM) and weak activity in each of the other four cell lines (Figure 42). A urea analog, 164, was synthesized by following the general synthetic procedure as shown in Scheme 19, ii. Compound 164 had comparable cytotoxicity in Caki-2, A549, and HL-60 but showed significantly potent cytotoxicity in HT-29 and PC-3 when compared to 163 (Figure 42). Therefore, urea serves as a suitable amide bioisostere. When the p-nitro group was excised, it resulted in more than a 3-fold decrease in cytotoxicity. When octyl and dodecyl groups were added to the urea moiety, the dodecyl analogs were more active compared to octyl. This is consistent with other studies of ceramide where biological activity was enhanced with increasing acyl chain length.(217,218) This is a known phenomenon in medicinal chemistry wherein enhanced lipophilicity increases activity to a certain limit.(219) Results showed that retention of stereochemistry on the backbone may not be essential for potent cytotoxic activity. However, this may not be certain because the 163 urea analogs containing (1R, 2R) and (1S, 2S) enantiomers displayed similar activity, while enantiomers of unsubstituted phenyl rings and 1-hydroxymethyls were inactive, making a conclusive comparison challenging. Overall, the urea motif appeared to serve as a suitable bioisosteric replacement of an amide for novel ceramide analogs.(216)
Figure 42
Figure 42. Structures of 163, B13, a ceramide analog tested for in vitro cytotoxicity against five human tumor cell lines, and 164, a more potent urea bioisostere.
The antitrypanosomal activities of novel derivatives against Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT), were explored.(220) Human African trypanosomiasis occurs in 36 nations of sub-Saharan Africa and is an insect vectored disease caused by Trypanosoma brucei gambiense which progresses slowly from early stage to late stage or can progress rapidly when caused by Trypanosoma brucei rhodesiense. In late-stage HAT, the central nervous system is infected and the disease becomes fatal if patients are left untreated regardless of the contributing parasite.(221) The compound 2-(2-benzamido)ethyl-4-phenylthizaole 165 (Figure 43) was one of 1035 compounds from a phenotypic high-throughput screen of 700,000 compounds that inhibited the growth of T. brucei in vitro at concentrations below 3.6 μM and was nontoxic to mammalian cells (Huh7). A total of 82 novel analogs were synthesized by Patrick and colleagues and tested against T. brucei rhodesiense STIB900 and L6 rat myoblast cells for cytotoxicity in vitro. It was found that 44 derivatives were more potent than 165 with antiparasitic IC50 values ranging from 9 nM to >300 μM in which eight of them displayed IC50 values below 100 nM. Overall, ureas were significantly more potent than amides in addition to being more selective for the parasite. From these, the most potent and selective for T. brucei rhodesiense was a piperidyl urea analog 166 with an IC50 = 0.0090 μM. Thirty-three compounds with IC50 values below 0.2 μg/mL were tested in mice infected with T.b. rhodesiense STIB900. Despite these compounds displaying in vitro potencies, none of them cured any infected mice, although seven compounds did cause a reduction in parasitemia by at least 97% compared to the untreated control group. Relapses occurred in all cases. Further analysis was taken in which the stability of 15 compounds in MLM and HLM, with and without the nicotinamide adenine dinucleotide phosphate (NADPH) cofactor, was evaluated to determine if metabolic instability was the contributing factor for the lack of in vivo efficacy. The SAR studies revealed that the incorporation of a piperidyl urea moiety (166) significantly improved the potency against T.b.brucei when compared to 165. However, compound 166 suffered from low metabolic stability in MLM (t1/2 = 1.6 min) and also was the least stable to HLM (t1/2 = 4.9 min) in comparison to 165 (Figure 43). These microsomal studies revealed that compound 166 collectively had poor metabolic stability and therefore was not further evaluated in vivo.(220)
Figure 43
Figure 43. Antitrypanosomal agent 165, an amide derivative, was further optimized to urea derivatives 166 and 167.
In order to improve metabolic stability while maintaining potency, further optimization was attempted. This led to more promising compounds based around urea derivatives of 2-arylbenzothiazol-5-amines, more specifically (S)-2-(3,4-difluorophenyl)-5-(3-fluoro-N-pyrrolidylamido)benzothiazole 167 (Figure 43). Herein modifications in other sites of 165 were performed, and in almost all cases except three analogs, the three-carbon bridge between the amide and thiazole nitrogen atoms of 165 was retained. Modifications were performed via replacement of the carbonyl oxygen of the amide with sulfur, various substituents on the piperidine ring of 166, and alkylation or unsaturation of the ethylene linker. Results showed that none of these provided any advantage regarding the antitrypanosomal activity or metabolic stability. Enhanced metabolic stability was observed only in the presence of benzoxazole- or benzothiazole-5-amino moiety in fused ring analogs. However, antitrypanosomal activity was only retained in benzothiazole derivatives. Thus, the ethylene linker played a role in the poor metabolic stability of initial thiazole analogs. From this series, 167 was discovered which exhibited good activity in vitro (T.b.brucei; EC50 = 0.0348 μM), had no detectable toxicity when tested in two human cell lines [human lymphoblast cells (CRL-8155) and HepG2], and possessed a half-life of >60 min in both MLM and HLM (Figure 43). The target compound 167 was prepared by reacting a primary amine (168) with triethylamine in dichloromethane. Triphosgene was added followed by the addition of (S)-3-fluoropyrrolidine hydrogen chloride (Scheme 21). Compound 167 was also tested in mice; oral administration of 5 mg/kg intraperitoneal (ip) dose resulted in Cmax = 23.34 μM and AUC = 13,254 min·μM with excellent brain penetration (brain concentration of 9.07 μM and brain/plasma ratio of 4.00). The compound was advanced to in vivo efficacy studies in which oral dosing cured 5/5 acute and chronic models of HAT, making it a representative lead for the future development of drugs combating this disease.(221)
Scheme 21
Scheme 21. Synthesis of 167, a Novel and Potential Drug for Human African Trypanosomiasis
In order to target the ThDP binding site of Escherichia coli pyruvate dehydrogenase complex E1 component (PDHc-E1), two novel “open-chain” linkers, comprising amide and urea functionality, were studied for their effect on E. coli PDHc-E1 inhibition. The pyruvate dehydrogenase complex (PDHc) catalyzes the conversion of pyruvate into acetyl-CoA, while PDHc-E1 catalyzes the first irreversible step of this multistep process. The PDHc-E1 protein has been reported to be a promising target for the development of fungicide and herbicide agents.(222) Several studies on small molecule inhibitors of PDHc-E1 have been reported, but they suffer from structural complexity and contain a highly charged pyrophosphate. Therefore, there is a need for the development of small molecules as inhibitors of PDHc-E1 that overcome these limitations. First, SAR studies revealed that placing iodine in the 5-position of the 1,2,3-triazole moiety of compounds under investigation had the potential to increase inhibitory and antifungal activity against E. coli PDHc-E1. Additionally, the linker was essential for biological activity, thus leading to the optimization of 1,2,3-triazole derivatives with amide and urea moieties as “open-chain” linker analogs of 169 (Figure 44). Amide and urea derivatives were evaluated for their in vitro inhibition of E. coli PDHc-E1. Most compounds had a good inhibitory activity with IC50 < 20 μM. These studies revealed that compounds with an amide linkage possessed inhibitory activity highly correlated to substituents on the benzene ring; electron-withdrawing groups led to more potent inhibitory activity, as seen in 170 (Figure 44). This compound possessing a 4-NO2 substituent resulted in the most potent inhibitory activity, IC50 = 3.58 ± 0.52 μM (Figure 44). Overall, the amide linkage has higher inhibitory activity than parent triazole 169. As for the urea linkage, inhibitory activity was improved compared to the corresponding amide derivatives with the same substituents, thus resulting in compound 171, which had the same potency as 170. The synthetic method utilized for the preparation of compound 171 is outlined in Scheme 22. He and co-workers tried to synthesize a urea derivative with a 4-NO2 in the benzene ring; however, they were unsuccessful. Next, they performed molecular docking studies that showed that the binding mode of 171 is similar to 170 in the active site of E. coli PDHc-E1 (Figure 45). However, the two NH groups of the urea form strong hydrogen bonds with Glu522; the oxygen of the phenoxy also hydrogen bonds with Leu264 which could be due to the increase in chain length afforded by the urea moiety. Overall, the amide and urea linkages have a beneficial effect on E. coli PDHc-E1 inhibition versus the 1,2,3-triazole derivatives.(222)
Figure 44
Figure 44. Structures of the amide (169) and urea (171) bioisostere derivatives of the triazole-based Escherichia coli PDHc-E1 inhibitor 169.
Figure 45
Figure 45. Graphical representation of the binding modes of 170 (A) and 171 (B) into the active site of E. coli PDHc-E1 displayed in ribbon. Ligands and residues are depicted by stick, while the hydrogen and coordination bonds are shown with dashed lines (green). Reproduced with permission from Bioorganic
& Medicinal Chemistry (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry), Volume 22, pp 3180–3186,
Scheme 22
Scheme 22. Synthetic Route To Access the Potent Urea Derivative 171, an E. coli PDHc-E1 Inhibitor
Carbamate Bioisosteres
ARTICLE SECTIONS
Ghosh and co-workers have described that a carbamate motif can be considered as structurally related to an amide–ester hybrid. Carbamates can modulate inter- and intramolecular interactions with target enzymes or receptors. Additionally, they induce a degree of conformational restriction as a result of the delocalization of nonbonded electrons on the nitrogen atom. Hydrogen bonding also occurs via the carboxyl group and NH backbone. Carbamates possess a pseudo double bond; thus, two isomers, syn and anti, can coexist. They display close similarity to amides; however, they prefer the anti-isomer. Ultimately solvent, concentration, salts, and pH influence the adaptation of syn and anti isomers in carbamates. Overall, carbamates possess very good chemical and proteolytic stabilities. They serve as amide bioisosteres in peptidomimetics due to their chemical stability and ability to permeate cell membranes. Carbamate-based prodrugs must undergo extensive hydrolysis in order to release the active drug at a suitable rate to achieve the desired activity profile.(223)
The global pandemic of HIV/AIDS was first identified in 1983–1984. The protease enzyme of HIV cleaves the kh and gag-pol polyprotein into its essential structural parts. Protease inhibitors block this enzyme, thereby preventing the development of the HIV virus. Saquinavir 173 (Figure 46) was approved in 1995 as the first HIV protease inhibitor.(224,225) Although 173 is a potent protease inhibitor, which is effective against both HIV-1 and HIV-2 proteases, this can also lead to reduced susceptibility to clinical resistance due to these enzymes being the most genetically divergent strains. Ghosh and co-workers investigated the replacement of the P2-asparagine of 173 with (2S,3′R)-tetrahydrofuranylglycine 174 which led to increased enzyme affinities for HIV-1 and HIV-2 proteases and significant enhancement of antiviral potency.(226) These compounds prevented HIV-1 in MT4 infected with 111b isolate; 174 was 3-fold more potent (CIC95 = 8 ± 4 nM) than 173 (CIC95 = 22 ± 7 nM). In HIV-2, 174 was 2-fold more potent (IC50 = 0.24 nM) than 173 (IC50 = 0.5 nM) (Figure 46).(227) An X-ray crystal structure of 173 bound to the HIV-1 protease showed that the carbonyl oxygen of the asparagine is within hydrogen bonding distance to the NH group within both Asp29 and Asp30, present in the S2 binding domain of the HIV-1 protease. On the basis of this, the authors hypothesized that the ether oxygen would conformationally constrain and lend its lone pairs for hydrogen bonding to the residues in the S2 region of the active site. A model for 174 was superimposed on the structure of 173, which revealed that the tetrahydrofuran oxygen of 174 is indeed in close proximity to the carbonyl oxygen of asparagine. Overall, replacing the P2-asparagine of 173 with (2S,3′R)-tetrahydrofuranylglycine 174 led to an over 4-fold increase in enzyme inhibition for HIV-1 (IC50 = 0.23 ± 0.1 nM) and HIV-2 (IC50 = 0.054 ± 0.027 nM), respectively.(228)
Figure 46
Figure 46. Potent HIV protease inhibitors incorporating carbamate bioisosteres.
To continue their studies of designing novel, cyclic ligands for the HIV-1 protease substrate binding site, Ghosh and co-workers introduced urethanes instead of N-terminus acyclic tert-butylurethane.(226) Incorporation of various 3-tetrahydrofuranyl- or 3-tetrahydropyranylurethanes as P2 ligands in hydroxyethylamine and hydroxyethylene series was developed. Compound 175 (IC50 = 160 nM) (Figure 46) bearing a tetrahydrofuranylurethane moiety exhibited more than an 18-fold potency increase relative to its BOC derivative (structure not shown) (IC50 ≥ 3000 nM). Replacing a BOC urethane with 3(S)-tetrahydrofuranylurethane (176) resulted in over a 10-fold increase in inhibitory potency (IC50 ≤ 0.03 nM) and prevented the spread of HIV-1 (CIC95 = 3 nM) (structure not shown). The synthetic route leading to compound 176 is delineated in Scheme 23, where 3-(S)-tetrahydrofuranyl succinimidyl carbonate was reacted with amine 177 in the presence of triethylamine to afford 176. It was concluded from this study that 3-tetrahydrofurans and pyrans are high-affinity ligands for the S2 binding domain of HIV-1 protease resulting in potent inhibitors.
Scheme 23
Scheme 23. Synthetic Route To Access 3-(S)-Tetrahydrofuranylurethane-Containing Analog 176, a Potent HIV-1 Protease Inhibitor
Inhibiting β-secretase may provide a promising target for AD.(229) On the basis of a β-secretase inhibitor 178 (Aβ40 (cell) IC50 = 0.082 nM) (Figure 47),(230) Peters and colleagues designed a series of carbamate derivatives of dibenzazepinone as potent and metabolically stable γ-secretase inhibitors.(231) First, they evaluated the potential of 178 as a lead structure by preparing close analogs, one of which was the carbamate analog 179 (Figure 47). However, 179 displayed poor activity (IC50 = 1500 nM). Despite this, it was found that a carbamate in place of an amide was tolerated in further synthesized compounds. Moreover, although 179 was a weak γ-secretase inhibitor, it gave rise to the possibility of deriving a stereogenic center from the chiral pool such as lactic acid. Thus, it could possibly prevent the separation of diastereomers in the process of inhibitor synthesis. Changing a malanomide analog to a carbamate 180 (IC50 = 1.7 nM) (Figure 47) gave an improvement in solubility and microsomal stability and led to reduced clearance in vivo. The synthetic procedure to obtain compound 180 is shown in Scheme 24. Arguably, a carbamate motif is biodegradable; however, in this case it was stable with plasma and buffer at various pH values (1.7, 4.7, and 7.8). At pH 12.8, slow degradation occurred (t1/2 = 57 h). In an in vivo AD model, both the malanomides and 180 dose-dependently increased the ratio of C-terminal fragment (AβPP) after oral administration with a minimal effective dose of three doses (3 mg/kg) over 2 days. Both the malanomide and carbamate analogs were potent γ-secretase inhibitors with single digit nanomolar inhibitory activity in vivo and were also efficacious in a mouse model of AD after oral administration.
Figure 47
Figure 47. Structures of parent amide 178, a γ-secretase inhibitor, and potent carbamate-based derivatives 179 and 180 for the treatment of AD.
Scheme 24
Scheme 24. Synthetic Route To Access the Dibenzazepinone-Based γ-Secretase Inhibitor 180
Substance P (SP) is an 11 amino acid molecule that preferentially binds to the neurokinin-1 (NK-1) receptor, where it acts as a neurotransmitter and neuromodulator in the central and peripheral nervous system. Substance P is broken down into several bioactive fragments; substance P 1–7 (SP1–7), a heptapeptide, is a major N-terminal metabolite that has been comprehensively evaluated. It has been shown to have high affinity to specific binding sites in the spinal cord and brain. Numerous reports propose that it may have its own putative receptor. Fransson and colleagues were able to demonstrate that it could induce antihyperalgesia in diabetic mice.(232) It is thereby suggested that SP1–7 peptidomimetics could have the potential to serve as therapeutic agents for neuropathic pain. Initially, alanine and subsequent N- and C-terminal modifications of SP1–7 and endomorphin-2, and subsequent truncation gave rise to the lead compound 182 (Figure 48). This compound had a more pronounced effect in diabetic mice than SP1–7 when administered intrathecally. Structure–activity relationship studies of dipeptide analogs and rigid analogs of H-Phe-Phe-NH2 revealed that two benzyl moieties in the (S, S) configuration and a primary amine at the N-terminal with a crucial primary amide function in the C-terminal were the structural motifs optimal in order to achieve high binding affinity. However, this pharmacophore led to high efflux of the compound. Therefore, it was investigated what pharmacophore was essential through the exploration of compounds with fewer hydrogen bond donors. The N-terminal of the basic phenylalanine in 182 (Ki = 1.5 nM) was exchanged for a more lipophilic benzyloxycarbonyl moiety giving rise to 183 (Figure 48). The synthesis of compound 183 was accomplished through the reaction of C-terminal activated benzyloxycarbonyl protected phenylalanine (184) with ammonia (Scheme 25). Compound 183 was then evaluated in an SP1–7 binding assay, which gave rise to a good binding affinity (Ki = 5.2 nM) while still maintaining interactions with the target. The in vitro profile of 182 displayed poor “drug-like” properties as a result of low membrane permeability, high in vitro clearance (Clint = 97.3 μL mim–1 mg–1) (Figure 48) and no measurable plasma protein binding. This could be due to rapid degradation in plasma; therefore, this compound was not further investigated in vivo. Compound 183, in which the N-terminal amine was replaced with a carbamate motif, resulted in improved membrane permeability (Papp = 31 × 10–6 cm/s), low efflux, and moderate in vitro clearance (Clint = 22.6 μL mim–1 mg–1) (Figure 48). Despite these promising results, compound 183 experienced hydrolytic cleavage in rat blood/plasma, inducing extrahepatic clearance, thus preventing good exposure after a single dose in rats. When tested in human plasma, this was not an issue. Compound 183 was further evaluated with different C-terminal groups (hydroxamic acid, acyl cyanamide, acyl sulfonamide, acyl hydrazine, and 1,3,4-oxadiazole) using a bioisosteric approach. Overall, these analogs showed moderate to good binding affinities for the SP1–7 binding site (IC50 = 4–60 nM). These C-terminally modified compounds were also evaluated for their uptake, metabolic stability, and permeability to determine the effect of bioisosterism on pharmacokinetic properties. When compared to 183, the rat plasma stabilities were improved for all analogs except two. Additionally, three out of the five showed a low risk of oxidative metabolism and comparable Clint to 183. Overall, isosteres provided compounds with increased permeability, low efflux, and good metabolic stability.(232)
Figure 48
Figure 48. Replacement of the amide bond in 182 with a carbamate moiety to afford compound 183, novel SP1–7 analogs as potential therapeutic agents for neuropathic pain.
Scheme 25
Scheme 25. Synthetic Route To a Carbamate-Based Dipeptide SP1–7 Analog (183)
Amidine Bioisosteres
ARTICLE SECTIONS
Very late activating antigen-4 (VLA-4), a key cell surface integrin, is expressed in circulating leukocytes. It plays a critical role in inflammation via the promotion of leukocyte attachment and extravasation from the vasculature into peripheral tissues. Thus, VLA-4 antagonists could be useful for the treatment of multiple sclerosis, rheumatoid arthritis, and asthma.(233) Kamenecka and co-workers previously reported potent and specific amide VLA-4 antagonists 185 and 186 (Figure 49).(234) These N-phenylsulfonylproline biphenylalanine derivatives suffered from poor pharmacokinetic properties such as low oral bioavailability (F < 10%) and high plasma clearance in rat (Clp > 90 mL min–1 kg–1) (Figure 49). This raised speculation of whether these deficiencies were a result of the amide bond, and so this group was either removed or modified. Bioisosteric replacement of the amide bond with an ester caused a 200-fold decrease in potency while N-methylation gave rise to a 4000-fold drop. Therefore, it was concluded that the NH was essential for potency. Removal of the amide carbonyl motif resulted in a 2000-fold reduction in potency. This could be the result of the secondary amine being too basic to engage in essential hydrogen bonding or as a result of a conformational change in the molecule leading to a reduction in potency. It was still unclear if the oxygen atom was needed, so Kamenecka and co-workers sought amidines as amide bond bioisosteres to help attenuate the basicity on the nitrogen group, thus giving rise to improved potency and pharmacokinetics. Results showed that changing the oxygen atom in 185 to an NH (187) resulted in almost equipotent VLA-4 inhibitory activity (Figure 49), thus confirming that the amide bond oxygen is not necessary for potency, but the amide oxygen or amide nitrogen can still act as a hydrogen bond acceptor. Next, the NH bond of 187 was modified by amalgamation with an EWG on the nitrogen linked with one methylene group (188). This modification did not produce significant improvement in antagonizing VLA-4; however, both compounds (187 and 188) displayed slightly better pharmacokinetic profiles than 185 and 186 (Figure 49). The synthetic procedure of amidine bioisosteres 187 and 188 is outlined in Scheme 26.(233)
Figure 49
Figure 49. Amidine as a bioisostere of the amide functionality in VLA-4 antagonists.
Scheme 26
Scheme 26. Synthetic Route To Access Amidine Derivatives as VLA-4 Antagonists
Thioamide Bioisosteres
ARTICLE SECTIONS
The thioamide and amide functional groups share the same number of atoms and valence electrons, which are arranged similarly. The thiocarbonyl bond is longer than a carbonyl bond. Additionally, the C–N bond in the thioamide is shorter in comparison to the amide due to the larger contribution of resonance. Two structural deviations of the thioamide from the amide do exist: there is a more rigid out-of-plane bending vibration mode due to the nitrogen in the thioamide, and there is an increase in rotational barrier across the C–N bond in thioamides over amides by 2–3 kcal mol–1. Thioamides, like amides and esters, can exist as cis and trans isomers. The proton affinity of sulfur in a thioamide (203 kcal mol–1) is greater than that of oxygen (199 kcal mol–1) in an amide. Despite this, thioamides are weak hydrogen bond acceptors compared to amides since this is negated by the unfavorable entropies that go with hydrogen bond formation in thioamides.(235)
Bacterial resistance is an emerging issue when combating bacterial infections and has led to the continuous search for novel antibiotics. Previously, Thorarensen and colleagues reported the optimization of anthranilic acid hit compound 190, which led to the discovery of lead compound 191 displaying potent broad-spectrum antibacterial activity (Figure 50).(236) This group sought to explore the role of the linker connecting the A- and B-rings in 191. They decided to take the amide bioisostere approach based on the following two hypotheses: the amide linker was involved in an essential interaction with the target and disruption of this would be detrimental to activity, and the purpose of the amide linker was to act as a conformational control element thereby linking essential pharmacophores. They proceeded to select functional groups that were successful amide bioisosteres through their ability to maintain essential recognition elements of an amide via incorporation of hydrogen bond acceptor or hydrogen bond donor properties. Some of their previous work revealed that electron-withdrawing groups (-Cl, -Br, -NO2, and -CN) at the 5-position on the A ring were interchangeable and resulted in similar antibacterial activity. Additionally, 3- versus 4-substituted B-rings resulted in analogs with similar activity; however, 3-substitution had a slight improvement in potency. The selection of a B-ring substituent was influenced by the fact that the corresponding amide illustrated reasonable antibacterial activity. Next, substitution patterns were picked on the sole basis of the ease of synthesis. The thioamide moiety as in 192 was readily available via reflux in toluene with compound 193 and Lawesson’s reagent. The hydrolysis of the ester fragment with treatment of lithium hydroxide gave rise to compound 192 (Scheme 27). The ability of the new linker to serve as an amide bioisosteric replacement was monitored based on its activity against Staphylococcus aureus. Results showed that the thioamide 192 (Scheme 27) was equipotent with its corresponding amide. The minimal inhibitory concentrations (MIC) were tested across five different bacterial strains, but improvements were seen in only three strains (Staphylococcus aureus UC 9218 (SAUR), Staphylococcus epidermidis UC 12084 (SEPId), and Haemophilus influenzae 30063 (HINF)) for the thioamide 192 in comparison to the amide 191 (Figure 50). However, the improvement in activity for the thioamide was not clear. Conversion from an amide to a thioamide is only a small change in linker construction. Nevertheless, results did show that removing this linker resulted in analogs devoid of activity. Replacing the linker with a five-membered ring heterocycle results in the abolishment of activity. Using an alkane caused faint antibacterial activity, but an alkene, more specifically an E-alkene, provided equipotent activity to its corresponding amide, suggesting a critical role in retaining bioactive conformation. It can be concluded that an amide is not necessary for activity but plays a role as a recognition element and adequately positions the aryl rings. Therefore, an amide can be replaced without significantly affecting MIC antibacterial activity of novel linkers.
Figure 50
Figure 50. Anthranilic acid lead 190, advanced lead 191, and alternative thioamide bioisostere 192 as antibacterial agents.
Scheme 27
Scheme 27. Synthetic Route To Access Thioamide 192
Trifluoroethylamine Bioisosteres
ARTICLE SECTIONS
The introduction of a trifluoroethylamine group [CH(CF3)NH] is an emerging mimic of the natural parent amide bond in a number of peptidomimetic compounds. In 2000, Zanda and co-workers published the first example of peptide mimics that incorporated a trifluoroethylamine group as a replacement for the amide moiety.(237) The trifluoroethylamine motif has the ability to reduce the basicity of the NH while preserving hydrogen bond donating properties, retains the backbone geometry of the amide bond (bond angle close to 120°), and has structural similarity with a tetrahedral proteolytic transition state (TS), and the C–CF3 bond is isopolar with the carbonyl bond.(238) An additional benefit is the sp3 hybridization of the trifluoroethylamine functional group that can influence the conformation of substituent groups into a target receptors’ active site, enhancing hydrogen bond strength. Zanda and co-workers replaced both a glycine amide bond and a malonamide to a partially modified retro-Ψ[NHCH(CF3)] peptide (Figure 51).(239) They also synthesized a Ψ[NHCH(CF3) retrothiorphan analog 197 (Figure 51) over the course of several steps starting with the reaction of N-trifluorocrotonoyloxazolidin-2-one (198) and l-phenyl alaninol (Scheme 28). Compound 197 was determined to be a potent and selective inhibitor of metalloproteinase neutral endopeptidase (NEP) which does not inhibit the related zinc proteinase, angiotensin-converting enzyme (ACE), and plays a key role in controlling blood pressure.(238) Compound 197 was evaluated for its inhibitory capacity toward NEP 24.11 achieving IC50 values greater than the thiophan parent scaffold, with Ki values over 4 M. Results proved that there was loss of NEP inhibition capacity when comparing compound 197 and its stereoisomers with (R)- and (S)-retrothiorphan (Ki = 2.3 nM and 210 nM, respectively). Despite these results, it was found that the trifluoroethylamine unit possesses high metabolic stability and restricts the molecule into accessible conformational states, thereby resulting in well-defined conformational motifs. As a result, it is only an effective replacement if the carbonyl group of the parent peptide is not involved in key hydrogen bonding with the receptor.(238)
Figure 51
Figure 51. Molecular structures of natural 194 and bioisosteric Ψ[CH(CF3)NH]Gly 195 and 196 peptides and (S,S) [NHCH(CF3)]-retro-thiorphan diastereomer 197.
Scheme 28
Scheme 28. Synthesis Route To Access Ψ[NHCH(CF3)]-retro-thiorphan 197
Successful replacement of an amide with a trifluoroethylamine isostere has progressed beyond peptidomimetics; it has also been used in the lead optimization of odanacatib, 202 (Figure 52), a highly potent and selective drug candidate for the inhibition of cathepsin K (Cat K).(240) Cathepsin K, a lysosomal cysteine protease, is abundantly expressed in osteoclasts where it is responsible for degradation of the bone protein matrix. Blocking secreted cathepsin K can help prevent bone loss without affecting the ability of osteoblasts to build bone and thereby enhancing bone strength and quality.(241) Thus, Cat K inhibitors can be used as a therapeutic treatment for osteoporosis. Initially, X-ray crystallography showed that in an irreversible dipeptide inhibitor of Cat K, the P1–P2 amide hydrogen bonds with the enzyme backbone involving the NH and carbonyl groups. However, the P2–P3 amide bond only forms one hydrogen bond to Gly66 with the NH while the oxygen points toward the solvent. Thus, the P2–P3 amide bond can be replaced with an isostere without having detrimental effects on potency. In order to identify a potent and selective inhibitor of Cat K, the initial lead 200 was synthesized (Figure 52). It proved highly selective over cathepsins B, L, and S in enzyme assays and displayed good PK properties.(242) However, further studies revealed that its lysosomotropic properties caused the loss of selectivity in cell-based assays, more specifically in a Cat S-dependent B cell line assay where it blocked antigen presentations. Overall, this initial lead compound resulted in reduced effective selectivity in whole-cell assays which could cause an increase in potential adverse effects in the clinic.(243) Black and co-workers found that not only an analog of compound 200 containing a trifluoroethylamine moiety at the P2–P3 amide enhanced potency and selectivity over other cathepsins but the resulting compounds were also stable to P1–P2 amide bond cleavage similar to dipeptide inhibitors. Introduction of a trifluoroethylamine bioisostere was found to be a viable substitution at the P2–P3 amide for inhibitors of Cat K. Optimization studies led to the replacement of the P2 amide bond with a trifluoroethylamine isostere; compound 201 showed nearly comparative Cat K inhibition as 200. Additionally, 201 was nearly 26,000-fold more selective for Cat K over Cat B (Figure 52).(244)In vivo studies of this compound showed it was orally bioavailable to rat, dog, and rhesus monkey; however, it had metabolic liabilities such as a short half-life (2 h) and clearance (7.5 mL min–1 kg–1) in monkey (Figure 52).(243) In order to minimize leucine hydroxylation, amide hydrolysis, and lactonization, the P1 and P2 residues were modified and led to the final drug candidate 202. The general synthetic route to obtain the trifluoroethylamine bioisostere 202 is outlined in Scheme 29, i. Compound 202 is a potent, selective, and neutral cathepsin K inhibitor that maintains excellent selectivity and activity in both enzymatic and cell-based assays. It has minimal effects on intracellular collagen accumulation compared to other cathepsin K inhibitors, balicatib and relacatib, with long half-lives in preclinical species.(240) The compound continued into clinical development for the treatment of postmenopausal osteoporosis and bone metastasis. It progressively increased bone mineral density over 5 years and reduced the risk of fractures in patients. However, development was discontinued before the filing of a new drug application (NDA) due to an increased risk of cardiovascular events and risk of stroke.(245)
Figure 52
Figure 52. Structures of 200 a reversible dipeptide inhibitor of cathepsin K, 201 a neutral cathepsin K inhibitor, and 202 a potent cathepsin K inhibitor containing the trifluoroethylamine bioisostere.
Scheme 29
Scheme 29. General Synthetic Route To Generate Trifluoroethylamine Bioisostere via a Trifluoroacetaldehyde Ethyl Hemiacetal
An example of where an amide replacement with the trifluoroethylamine moiety affects selectivity of a drug toward different targets can be appreciated with telaprevir, 205. It is a first-generation peptidomimetic and potent hepatitis C virus (HCV) NS3 protease inhibitor with IC50 = 70 nM (Figure 53). Moreover, 205 has the ability of inhibiting other cysteine proteases such as cathepsin B with an IC50 of approximately 210 nM and is also an antiviral agent, EC50 = 210 nM in the replicon. Replacing the P4 amide moiety with a trifluoroethylamine surrogate identified two active inhibitors of cathepsin S with IC50 = 2 nM and 0.6 nM for compounds 206 and 207, respectively (Figure 53). However, in contrast to the unfluorinated parent compound 205, compounds 206 and 207 only exhibited a weak inhibition of HCV NS3 with 34% and 29% inhibition at 25 μM in the HCV replicon, respectively, despite the structural changes being remote from the active site.(16)
Figure 53
Figure 53. Structures of 205, a potent hepatitis C virus (HCV) NS3 protease inhibitor, and trifluoromethylated-containing cathepsin S inhibitors 206 and 207.
Bioisosteric replacement of an amide with a trifluoroethylamine moiety was examined in the design of β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors. Inhibitors containing a P1 or P2 amide motif exhibit high efflux transporter liability along with metabolic lability.(246) This was attributed to the release of aniline upon amide cleavage in vivo, thereby potentiating toxicity after metabolic activation. Butler and co-workers sought to identify an amide replacement that provided excellent potency but avoided the aniline structural motif and its toxicity. The X-ray cocrystal structure of a related BACE-1 inhibitor analog, compound 208 (Figure 54), showed that the amide NH is positioned in such a way that it engages with the backbone carbonyl of the Gly230 residue in order to partake in a critical hydrogen bonding interaction. Therefore, preservation of the NH of the aniline is necessary. It was found that the planar aniline moiety has sp3 nature on the benzylic carbon resulting in an orthogonal arrangement of the C–N bond relative to the fluorophenyl P1 ring, facilitating an optimal geometry for hydrogen bonding to Gly230. Due to uncertainty of what structural motifs were necessary, a parallel synthesis was performed in order to evaluate the SAR for BACE-1 which identified an ethylamine analog. This analog showed modest improvement in BACE-1 cell-free assay potency with IC50 = 13.9 μM. However, it has a more potent increase in whole-cell assay potency of about 1000-fold. This was attributed to the basicity of the analog which increases the tendency for accumulation into the endosome, an acidic intracellular compartment where BACE-1 resides. Further optimization focused on utilization of electron-withdrawing groups and incorporation of branched amines to further enhance potency. In due course, a CF3-cyclopropane derivative, compound 209 (Figure 54), was synthesized via reductive amination with 1-(trifluoromethyl)cyclopropan-1-amine, followed by the removal of the amidine protecting group (Scheme 30). Compound 209 maintained good potency in both BACE-1 cell-free assay (IC50 = 0.0069 μM) and whole-cell assay (IC50 = 0.018 μM) and overall an optimal balance of properties. A cocrystal structure of compound 209 in BACE-1 was obtained, and results showed that the thioamidine and difluorophenyl ring are orientated similarly to previously described BACE-1 inhibitor structures. The difluorophenyl occupies the S1 pocket as predicted, and the benzylic amine substituent adopts an orthogonal orientation toward the plane of the difluorophenyl P1 group in order to involve the carbonyl of Gly230. Results showed that improvements in BACE-1 cell-free assay potency using the CF3-containing lead was due to the CF3 group pointing toward and filling the S3 pocket while the cyclopropyl moiety fills a lipophilic pocket at the interface of the S1 and S3 pockets. In the end, compound 209 possessed significant inhibition activity toward cytochrome P450 subtype 2D6 (CYP 2D6) and development was discontinued.(246)
Figure 54
Figure 54. Structures of 208, an amide-based BACE-1 inhibitor, and CF3-cyclopropane bioisostere BACE-1 inhibitor 209.
Scheme 30
Scheme 30. Synthetic Route To Access Compound 209, a BACE-1 Inhibitor
An amide bond replacement on a malonyl moiety by an amide surrogate trifluoroethylamine was employed in the identification of novel receptor tyrosine kinases (RTKs) inhibitors, more specifically malonamide-type dual inhibitors of the vascular endothelial growth factor receptor-2 (VEGFR2) and c-Met receptors. Gaudette and colleagues initially investigated what changes were suitable for VEGFR2 and c-Met enzyme inhibition via initial SAR studies of compound 212, the parent malonamide (Figure 55).(247) First, the left-hand side of compound 212 was left unchanged and one amide moiety of the malonamide head group was replaced by a trifluoroethylamine moiety on the eastern side. Results showed that replacement of the eastern amide bond of the parent malonamide by the trifluoroethylamine moiety led to 23-fold and 11-fold decrease in activity for c-Met (IC50 = 0.70 μM) and VEGFR2 (IC50 = 0.21 μM), respectively, compared to compound 212 (IC50 = 0.03 μM and IC50 = 0.02 μM for c-Met and VEGFR2, respectively). The decrease in activity in VEGFR2 and c-Met could be due to the steric clash between the CF3 group and hydrophobic back pocket of the kinase active site and/or the loss of the carbonyl group, a strong hydrogen bond acceptor in compound 212. Replacement of the western amide bond by a trifluoroethylamine group caused a 4-fold decrease in activity against c-Met (IC50 = 0.12 μM). However, the compound showed similar VEGFR2 inhibitory activity (IC50 = 0.01 μM) as compound 212. The same observations were seen in a pyrimidine-based series, compound 213 which was found to be of highly selective and potent for VEGFR2 (IC50 = 0.04 μM). It was also profiled against a set of eight kinases where it was also highly selective for VEGFR3. Lastly, there was a significant effect on VEGF-dependent angiogenic activity where there was inhibition of VEGF-dependent proliferation of human umbilical vein endothelial cells (HUVEC). Replacing an amide moiety of a malonamide head group by a trifluoroethylamine led to the identification of novel, potent, and selective inhibitors of VEGFR2 enzyme. Compound 213 was synthesized over the course of several steps starting with the coupling of a corresponding amine with trifluoroacetaldehyde ethyl hemiacetal (Scheme 29, ii).(247)
Figure 55
Figure 55. Structures of parent malonamide 212 and selective and potent VEGFR2 inhibitor 213.
Sulfonamide Bioisosteres
ARTICLE SECTIONS
Sulfonamide functional groups are structurally related to amides in which the carbonyl moiety is replaced with an isosteric SO2 group. As in amide bioisosteres, sulfonamides are known to increase water solubility and could provide additional HBAs. Lim et al. reported a urea analog of B13, an aromatic ceramide analog with a phenyl ring in lieu of an alkenyl chain, that exhibited slightly more potent cytotoxicity compared to 163 (Figure 56). As previously mentioned in the urea bioisosteres section of this paper, results indicated that the urea appears to serve as a bioisostere of the amide.(216) A series of novel d-erythro ceramide analogs with alkylsulfonamido chains were synthesized and evaluated for their cellular toxicity against human tumor cell lines HeLA, Caki-2, PC-3, and HL-60. Modest cytotoxicity (IC50 = 48 μM) was displayed by 163 against HL-60 leukemic cells. An aromatic sulfonamide ceramide analog, 214, was synthesized via the coupling of the acid (216) and amine (215) with HOBt and EDCl (Scheme 31). In vitro evaluation showed that compound 214 had comparable cytotoxicity in Caki-2 (IC50 = 103 μM) and HeLa cancer cells (IC50 = 65 μM) but the greatest potent cytotoxicity in HL-60 leukemic cells (IC50 = 28 μM) (Figure 56). Further comprehensive analysis of the sulfonamide ceramides is needed; however, their cytotoxic properties appear to be cancer cell specific due to their structural similarities to 163. The introduction of a para-halogen onto the phenyl ring of d-erthyro ceramide analogs resulted in compounds with comparable or somewhat lower activity than unsubstituted phenyl ceramide analogs. Variations in the alkyl sulfonyl chain length had a more significant influence on the activity of aromatic ceramide analogs, more specifically, an aromatic sulfonamido ceramide analog.(248)
Figure 56
Figure 56. Structures of amide 163 and an aromatic sulfonamido ceramide bioisostere with more potent cytotoxic activity.
Scheme 31
Scheme 31. Synthetic Route To Access the Aromatic Alkyl Sulfonamido Ceramide Analog 214
The human isoprenylcysteine carboxyl methyltransferase (hIcmt) is a promising anticancer target. Proteins contain a C-terminal sequence motif called Caax box (where C is cysteine, aa is an aliphatic residue, and X is one of several amino acid residues). These motifs are post-translationally modified for cellular targeting, most common being membrane association. The protein K-Ras is one of the >120 proteins containing a Caax box; it undergoes farnesylation, endoproteolytic cleavage of the -aaX residues, and methyl esterification of the free carboxylate of the prenylated cysteine by isoprenylcysteine carboxyl methyltransferase (Icmt). When mutant K-Ras is in the constitutively active form in the GTP-bound conformation, it results in tumorigenesis. Inhibition of human Icmt has been thought of as blocking the activity of oncogenic Ras. N-Acetyl-S-farnesyl-l-cysteine (AFC) is a substrate for hIcmt, and previous work by Majmudar and co-workers has shown that amide modified farnesyl cysteine analogs (AMFCs) are low-micromolar inhibitors of hIcmt. No structural information on hIcmt exists, thereby possessing a challenge in designing Icmt inhibitors. It was hypothesized by Majmudar and co-workers that a bioisosteric replacement of an amide bond in AMFC would give rise to molecules with retained interaction with hIcmt and provide more insight on inhibition requirements. Compound 217 (Figure 57) represents one of the most potent AMFCs (IC50 = 4.3 μM) synthesized by Donelson et al.(249) The goal was to determine the structural requirements for hIcmt inhibitors by prenylated cysteine derivatives with a sulfonamide bioisostere. Sulfonyl chlorides with varying electronic character, steric bulk, and alkyl aromatic scaffolds were incorporated. These new analogs were evaluated as substrates and inhibitors of human Icmt using a vapor diffusion assay (VDA). Results showed that no sulfonamide modified farnesyl cysteine analogs (SMFCs) are effective substrates but rather serve as moderate inhibitors of hIcmt. Compound 218 was obtained via reaction of a corresponding primary amine and sulfonyl chloride in the presence of sodium carbonate using dioxane as a solvent (Scheme 32, i). Compound 218 displayed 64% hIcmt inhibition at 10 μM using 25 μM AFC as the substrate with an IC50 = 8.8 ± 0.5 μM (Figure 57). It was hypothesized that the reason why SMFCs are not substrates for hIcmt is due to the reason that the amide bond or the carbonyl carbon is necessary for substrate activity. Additionally, SMFCs do inhibit Icmt but have varying strength of inhibition. Poor hIcmt inhibitors were analogs containing highly bulky or rigid motifs. Compounds with electron-withdrawing groups were more potent than electron-donating groups; however, some exceptions do exist. A planar bulk next to the sulfonamide bond enhances inhibitory activity. The effect of the prenyl group was also evaluated, but none of these compounds exhibited substrate activity at 25 μM and were poor inhibitors of hICmt compared to their farnesyl analogs. As a result, the farnesyl group is highly important for hIcmt inhibition by SMFCs. Overall, the determining factor for hICmt inhibition by SMFCs is related to the presence of the farnesyl chain, resulting in a specific binding interaction rather than just acting as hydrophobic bulk. Stereochemistry at the α carbon did not play a significant role in hIcmt inhibition by SMFCs. When deviating from the carboxylate group, there is a reduction in hICmt inhibitory activity; however, this needs to be evaluated further with more analogs. Overall, the sulfonamide bond is a viable bioisosteric replacement for the amide bond in AFC derived hICmt inhibitors.(250)
Figure 57
Figure 57. Phenoxyphenyl farnesylcysteine 217 and sulfonamide-modified farnesylcysteine (SMFC) analog 218, as hIcmt inhibitors.
Scheme 32
Scheme 32. General Synthetic Procedure To Obtain Sulfonamide Bioisostere
Natural products have a successful history of being a source of new therapeutics as a result of their high chemical diversity and biochemical specificity.(251) Capsaicin 24, the main pungent and irritating component of chili peppers, was reported to selectively inhibit the growth of various tumor cell lines. Early work gave rise to controversy regarding its mutagenic and carcinogenic abilities; however, recent studies have proven that it induces apoptosis in a large number of tumor cell types and that capsaicinoids possess in vitro and in vivo antitumor activity. Thus, 24 has the potential of serving as a lead against malignant tumors. However, some limitations such as its poor stability, attributed to the liable amide motif, and strong pungency limit its use and application in drug discovery.(252) The pungency of 24 is related to its ability to directly promote stimuli on transient receptor potential vanilloid subtype 1, thus causing Ca2+ influx and subsequently nociceptive hyperpolarization. The molecular mechanisms of capsaicin-induced cell death are still uncertain. Despite this, the capsaicinoid scaffold gave rise to molecules exhibiting improved physiochemical and pharmacological profiles. Ferreira and colleagues have investigated the optimization of capsaicin-like analogs as potential anticancer agents. The development of these compounds began with structural changes to the 24 structure (Figure 58), which was divided into three parts: the methylcatechol group (region A), the amide bond (region B), and an alkyl side chain (region C). In region A, cyclization was investigated which converted the methylcatechol group to the 1,3-benzodioxole bicyclic motif. This modification could give rise to important advantages since the benzodioxole system is a privileged structure for substances containing antitumor activity.(253) In the first analog series, the amide bond linker (region B) was maintained or underwent a bioisosteric replacement by an ester, and the alkyl side chain (region C) was replaced by several alkyl/aryl groups to preserve the hydrophobic nature of this region. In the first series, amide (222) or ester analogs (223) (Figure 58) revealed that some of these analogs had equipotent cytotoxicity to 24 against Mus musculus skin melanoma cells (B16F10) and M. D. Anderson metastasis breast adenocarcinoma (MDA-MB-231). Despite this, these analogs suffered from poor chemical stability, as did 24. The sulfonamide group, known to be very stable against chemical hydrolysis and other physiochemical degradation processes, was used as a bioisosteric replacement of the amide and ester linkers to afford 224–226 (Figure 58).
Figure 58
Figure 58. Capsaicin (24) and step by step development of novel capsaicin-like bioisosteric analogs 222–226.
Additionally, the use of the sulfonamide group was supported by the results of exploratory data analysis wherein the designed sulfonamide analogs clustered with the same set of compounds that had previously shown activity. Thus, aryl and alkyl sulfonamide bioisosteres were synthesized, giving rise to 224 and 225 (Figure 58). These analogs were a success because they resulted in slightly superior cytotoxic activity compared to 24, displayed improved stability, but had poor solubility. In order to overcome this pitfall, a less hydrophobic sulfonamide analog was designed in which the eight-methylene unit of 225 was truncated to contain a four-carbon alkyl chain 226 leading to increased aqueous solubility. Compound 226 was synthesized by reacting a corresponding primary amine and sulfonyl chloride in the presence of sodium carbonate and water (Scheme 32, ii). A theoretical approach was taken in order to find more energetically favorable conformations for 24 and 226, calculate molecular properties, and gain insight on SAR.(252) Next, the cytotoxic effects of 226 on MDA-MB-231 and human mammary epithelial cells (MCF10A) were evaluated. Results illustrated that both 24 and 226 both decreased the viability of MDA-MB-231 cells with IC50 values of 120 and 87 μM, respectively; however, 226 is potently more cytotoxic. Additionally, MCF10A cells were more resistant to treatment with 226 (IC50 = 198 μM) and also induced a change in cell morphology. Results indicated that 226 is an antitumor candidate with a cytotoxic mechanism. This new capsaicin analog was capable of interrupting cell-cycle progression via S-phase arrest and inducing cell death in MDA-MB-231 cells and apoptosis via the downregulation of the antiapoptotic Bcl-2 protein. Results also showed that 226 leads to apoptosis through caspase-3 cleavage in the death-inducing signaling complexes, TRAIL-R1/DR4 and TRAIL-R2/DR-5. In vivo results also indicated that 226 has antitumor properties as it was more effective (133.4 ± 24. 5 mm3) than 24 (281.3 ± 78.5 mm3) in reducing mean tumor volume and impairing tumor progression in the MDA-MB-231 model of breast cancer (Figure 58). Overall, the activity of 226 against MDA-MB-231, a well-established breast cancer model, and its lower pungency suggest its promising role as an anticancer agent for breast cancer.(252)
Novel irreversible HIV-1 protease inhibitors containing sulfonamide and sulfone groups as amide bond bioisosteres were discovered.(254) Biotech Research Institute, Korea, reported an irreversible inhibitor 227 (Figure 59) with IC50 = 20 nM containing an epoxide moiety as an active site isostere. The authors designed inhibitors with improved potency and fewer peptide bonds.(254) First, the replacement of the amide carbonyl group in the C-terminus in compound 227 with sulfonamide occurred since the hydrogen bonding between inhibitor and water in the enzyme was reported. The sulfonamide group would be able to maintain this hydrogen bonding as well as improve stability against amide hydrolysis by proteolytic enzymes. Next, the P2 site was taken into account for the design of new inhibitors since the pocket size of P2 is large in order to fit asparagine and valine. Therefore, replacing asparagine with suitable amphiphilic groups could increase the potency of inhibitors. Thus, the following modifications were made: inserting a sulfonamide for the P1–P2 amide bond and a sulfone group for the P2 asparagine, as seen in 228. The sulfonamide bioisostere (228) installation was achieved through the use of 3-chloropropane-1-sulfonyl chloride which is commercially available. Two sulfonamide bioisosteres of 227 were designed (229 and 230) (Figure 59). However, both of these bioisosteres were not the most potent of the series (IC50 = 30 nM and 20.2 nM, respectively). Results revealed that 228 was an inhibitor with high affinity, irreversibility, and high potency (IC50 = 6.6 nM) which could serve as a potential chemotherapeutic agent for the treatment of HIV.
Figure 59
Figure 59. Novel irreversible HIV-1 protease inhibitors encompassing sulfonamide and sulfone as amide bioisosteres.
Phosphonamidate Bioisosteres
ARTICLE SECTIONS
The RNA-dependent RNA polymerase (RdRp) of the hepatitis C virus, also known as nonstructural protein 5B (NS5B), is essential for the synthesis of viral RNA.(255) The protein has no functional equivalent in the mammalian system, and thus it is a target for inhibition by both nucleoside and non-nucleoside inhibitors. The 3D structure of RdRp suggests that NS5B has a cupped right-hand-like structure with a finger, palm, and thumb domain.(256) Several drugs such as filibuvir and lomibuvir bind to the thumb domain, whereas dasabuvir, GSK5852, HCV-796 bind to the palm domain.(257,258) Phosphonamidate bioisosterism has been reported to represent a new class of non-nucleoside inhibitors of HCV NS5B. The sulfonamide and amide groups were modified in the small molecules, 231 and 232 (Figure 60), respectively, which are non-nucleoside NS5B inhibitors that bind to the allosteric site 2 of the thumb domain of the HCV viral polymerase (Figure 61) .(259)
Figure 60
Figure 60. Non-nucleoside NS5B inhibitors (except 233), containing the phosphonamidate group as an amide bioisostere (233, 234, and 235).
Figure 61
Figure 61. Ribbon structure of NS5B HCV viral polymerase. Reproduced with permission from Bioorganic & Medicinal Chemistry Letters (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry-letters), Volume 26, pp 4536–4541,
Compound 232 had potent activity in genotypes 1a and 1b infections in preclinical trials. In order to test the hypothesis of phosphonamidate bioisosterism, two compounds, 233 and 234, were synthesized and evaluated for inhibition of HCV replication in the HCV replicon luciferase assay and inhibition of the 1b-J4 HCV NS5B polymerase.(259) Only compound 234 produced a modest inhibition of the NS5B polymerase (IC50 = 3.74 μM). Subsequently, detailed SAR investigations either on R1-R2-R3-R4-substitutions or on the thiophene moiety were conducted to determine the effect on the potency of this new phosphonamidate class of compounds. Many analogs, with varying substituents, were synthesized and evaluated, and ultimately, compound 235 was identified as the most active analog, with efficacy greater than that of the parent compound, 232. Scheme 33 describes the key synthetic route to generate the phosphonamidate bioisostere as in compound 235. Compound 235 had broad genotype profile: IC50 = 0.0099 μM, 0.2538 μM, 0.1809 μM, and 0.0257 μM for genotypes 1b, 2a, 3a, and 4a, respectively. Furthermore, 235 had high selectivity index with subnanomolar potency in the replicon assay (EC50 = 0.0004 μM) without producing cytotoxicity. Cocrystallization studies of 235 complexed with the viral NS5B indicated that the inhibitor is hydrogen bonded through the carboxylate functional group to the main chain of Ser476 and Tyr477 and to the side chain of Arg 501 with the oxo function of the phosphonamidate, confirming its interactions with the viral protein in the thumb 2 domain of NS5B (Figure 62). Compound 235, designated IDX17119, was selected for further preclinical and PK studies. Overall, the phosphonamidate proved to be a viable bioisosteric replacement for the amide function in developing potent non-nucleoside NS5B inhibitors.
Figure 62
Figure 62. Cocrystallization image of 235 complexed with the viral NS5B (PDB code 5CZB). Reproduced with permission from Bioorganic & Medicinal Chemistry Letters (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry-letters), Volume 26, pp 4536–4541,
Scheme 33
Scheme 33. Synthetic Route To Access 235
Ester Bioisosteres
ARTICLE SECTIONS
Geometrically an ester and amide are comparable. As with the resonance of an amide, in an ester, the lone pair of electrons on the oxygen delocalizes into the antibonding orbital of the ester carbonyl group. Similar to what happens with amides, the electron delocalization results in cis and trans isomers. The trans conformation of an ester is more stable than the cis conformation, as seen with amides. Additionally, esters and amides differ based on hydrogen bond formation, thus affecting protein folding and stability. Esters are weak hydrogen bond acceptors and cannot hydrogen bond-donate. In addition to this, esters are vulnerable to hydrolysis in vivo.(235) Amide isosteres can modulate polarity and bioavailability, while esters are used to address metabolism issues due to their vulnerability to cleavage in vivo, most often forming the cleavable component of prodrugs.(16)
Opioids are a common drug for the treatment of moderate to severe pain. The three major subtypes of opioid peptide receptors are μ (MOPr), δ (DOPr), and κ (KOPr). Leu-enkephalin (238) (Figure 63) is an agonist for the DOPr. However, 238 suffers from short half-life and high hydrophilicity, thereby hampering its ability to serve as a druggable compound. Additionally, enkephalins are rapidly metabolized by peptidases in the body as a result of their amide bonds and therefore cannot cross the blood–brain barrier (BBB) and reach opioid receptors in the central nervous system.(260) Previously Rochon and co-workers have reported the effects of replacing the amide bonds in 238 with E-alkenes. When doing so, the replacement of the first amide bond by E-alkene did not affect the biological activity of 238. Therefore, it was concluded that this bond is not involved in intramolecular or intermolecular interactions with the DOPr.(260)
Figure 63
Figure 63. Structures of peptide 238 and analogs in which the amide bond was replaced by an ester 239 or N-methylamide bond 240.
Next, they sought to employ other amide bioisosteres including esters and N-methyl amides. The reason for the choice of these motifs, in particular, is their potential to act as hydrogen bond acceptors and not as hydrogen bond donors. The N-methyl group introduces a steric bulk, thereby distorting the planarity of the amide and restricting the conformation around the modified amide. An ester functional group is a better mimic of a peptide bond since it does not undergo many geometric alterations; however, the partial double bond nature of the ester bond is not as pronounced as the amide bond. Thus, esters are more structurally flexible. Rochon and co-workers replaced all of the amide bonds of 238 with an ester or an N-methyl amide. To evaluate the ability of each compound to bind the DOPr, competitive binding assays using GH3/DOPr cell membrane penetration were used. Results showed that replacing the fourth amide bond with an ester (239) or N-methyl amide (240) gave compounds with similar affinities to that of 238 (Figure 63). Compound 240 was synthesized by a multistep peptide approach where N-methylated leucine amino acid starting material was commercially available. When the third amide bond of 238 was replaced by an ester, most of the affinity for the DOPr was retained (Ki = 34 ± 17). The phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) is used as an indicator of a compound’s ability to act as an agonist. The activation of the DOPR by an agonist stimulates the rapid and transient phosphorylation of ERK1/2. However, the maximal effect of 238 is 5 min after stimulation; therefore, compounds were evaluated after 5 min of stimulation with varying concentrations (10–9 to 10–5 M). Compounds 239 and 240 at concentrations of 10–7 M produced significant phosphorylation of ERK1/2 similar to that of 238.
Previously, this group reported the internalization of fluorescent chimeric DOPr (DOPr-GFp) in transfected DRGF11 cells in order to screen for active compounds. Compounds 239 and 240 were measured for their ability to induce internalization of DOPr-GFR. At 1 μM, 238 produced an internalization that was visually seen within 5 min and complete by 30 min. The level of internalization by 239 and 240 was similar to that of 238. These compounds were also tested for their ability to inhibit the electric-field induced contractions of the mouse vas deferens. Compound 240 has the greatest activity (EC50 = 35 ± 14 nM) compared to 240 and 238 (EC50 = 140 ± 5 nM and EC50 = 74 ± 1 nM), respectively. A goal of these 238 analogs was their ability to cross the blood–brain barrier; therefore, their lipophilicity was assessed. On the basis of all the modifications, the N-methyl amide resulted in compounds with the highest lipophilicity. Compounds 239 and 240 had high total polar surface area (tPSA) values in comparison to CNS acting drugs. Results also indicated that compound 240 had an increase in half-life (t1/2 = 10.7 min) compared to 238 (t1/2 = 4.6 min), which is due to the replacement of the fourth amide bond with an N-methyl amide function, thereby increasing the stability of the third amide bond. On the other hand, when an ester is introduced to 239, there was surprisingly little effect on the half-life (t1/2 = 3.3 min). These results showed that the systematic replacement of amides with bioisosteres such as an ester and N-methyl amide was an efficient way for designing novel peptide analogs of 238.(260)
Olefin Bioisosteres
ARTICLE SECTIONS
The bioisosteric replacement of a peptide bond with a nonhydrolyzable alkene functional group has been used to improve the “drug-like” properties of many parent compounds. The alkene bioisostere has been shown to mimic the planar geometrical features, but not the electronic and electrostatic properties, of an amide bond.(261,262) The bond lengths and angles of an alkene are virtually identical to an amide. In contrast, an alkene does not have hydrogen bonding capacity due to the absence of heteroatoms.(235) Furthermore, the value of the dipole moment is higher for an amide bond (3.6 D) than for an alkene (0.1 D).(263) Several studies have reported that the replacement of an amide bond with an alkene bioisostere produces molecules that are efficacious. For example, dihydrouracil analog 241 is a potent inhibitor of the RNA-dependent RNA polymerase, NS5B protein of the hepatitis C virus genotypes GT1a (EC50 = 51 nM) and GT1b (EC50 = 19 nM).(264) However, this compound had inherent pharmacokinetic issues; for example, 241 was rapidly cleared from plasma and thus had poor oral bioavailability (F = 1.4%) in rats. These results could be explained by the low aqueous solubility (<1.5 μM at pH 7.2) and poor membrane permeability of 241. Modification of the amide linker in 241 with one that lacked one or both hydrogen bonding groups enhanced the overall membrane permeability potential.(265) In order to identify a more potent HCV NS5B polymerase inhibitor with improved PK properties, the amide linkage was successfully replaced with a trans olefin, yielding compound ABT-072 (242) (Figure 64). The olefination of aldehyde group in 243 with diethyl (4-nitrobenzyl)phosphonate followed by the nitro reduction and methanesulfonylation gave 242 (Scheme 34). In the HCV genotype 1 (GT1) replicon assay, 242 had a greater potency for both the GT1a (EC50 = 1 nM) and GT1b (EC50 = 0.3 nM) polymerase compared to the parent compound 241.
Figure 64
Figure 64. Amide to trans olefin bioisosteric replacement leading to the clinical candidate 242.
Scheme 34
Scheme 34. Synthetic Route To Access 242, a Non-Nucleoside HCV NS5B Polymerase Inhibitor
Moreover, in PK studies, the plasma clearance of 242 was significantly decreased, thereby producing greater oral bioavailability in both rat (5 mg/kg, per oral (po), t1/2 = 3.1 h, and F = 44%) and dog (2.5 mg/kg, po, t1/2 = 5.4 h, and F = 86%). On the basis of these results, compound 242 was nominated for clinical studies. Pharmacokinetic studies in healthy human subjects indicated that 242 achieved maximum concentration within 5–9 h in plasma, with a mean terminal phase half-life of 7–9 h. Subsequently, phase II trials indicated that 242 was efficacious for treating genotype 1 infected HCV patients in combination with the other HCV protease inhibitor such as ritonavir, as well as ribavirin.
The calcitonin gene-related peptide is a 37 amino acid neuropeptide that has been shown to mediate various biological functions such as vasodilation and nociception.(266) The CGRP is released from sensory nerves and plays an integral role in the pathophysiology of migraine.(267) (E)-Alkene bioisosterism was used to develop acyclic CGRP antagonists, where the metabolically unstable central amide bond in a previously developed compound, 244 was replaced with an E-alkene linked to a substituted pyridyl moiety (245) (Figure 65).(268,269) Compound 245 was synthesized via palladium-catalyzed Heck coupling reaction with an unsaturated halide (246) and an alkene (247). The general synthetic procedure is delineated in Scheme 35. These molecular structural changes substantially improved the bioavailability and pharmacokinetic profile of compound 245 in rats compared to 244 while maintaining antagonist activity at the CGRP receptor.
Figure 65
Figure 65. Example of the replacement of a central amide of an azaoxindole derivative (244) with an E-alkene moiety 245.
Scheme 35
Scheme 35. General Synthetic Route To Access Alkene Bioisosteres
In 2007, Thorarensen et al. explored the SAR of the previously discovered lead compound, 249, and newly synthesized anthranilic acid derivatives(270) to elucidate the role of the linker connecting the two important pharmacophoric aryl A and B rings for antibacterial efficacy.(236) The amide linker in 249 was successfully replaced by several amide bioisosteres, and the E-alkene-containing analog 250 was found to have significantly lower MIC values, particularly in Staphylococcus aureus UC9218 and Staphylococcus epidermidis UC 12084 (SEPId) (Figure 66), than the parent compound 249. The general synthetic method showing Wittig olefination of an Wittig reagent (methyl 2-((bromotriphenyl-λ5-phosphaneyl)methyl)-5-cyanobenzoate) with an aldehyde (251) is described in Scheme 36, i. Overall, results suggest that the amide may not be essential for bioactivity, and it perhaps only keeps the pharmacophoric elements at the defined distances. Thus, an amide can be dispensable without causing a significant decrease in MIC values.
Figure 66
Figure 66. Structural modification of an amide linker in 249 to an E-alkene in 250 that joins A and B rings.
Scheme 36
Scheme 36. General Synthesis of E-Alkene Bioisosteres from Respective Aldehyde
In another study exploring the modification of amide to alkene, utilizing amylin (20–29) as a parent structure, Brouwer and co-workers reported the synthesis of alkene dipeptide/alkene dipeptidosulfonamide isosteres using a solid phase cross metathesis method.(271) Amylin, or human islet amyloid polypeptide, is a peptide hormone composed of 37 amino acids, where amylin (20–29) refers to the highly amyloidogenic region that is involved in the pathogenesis of type 2 diabetes. The modification in amylin (20–29) to yield compound 254 was postulated to be beneficial in determining the peptide backbone interactions and peptide stabilization in enzymatic degradation. Given that the alkene moiety closely resembled the geometry of the amide bond and that the amalgamation of a sulfonamide bond may increase the flexibility of the backbone, the authors transformed the amide function (at positions 27 and 28) of 254 into the alkene derivative 255 and the alkenesulfonamide (256) dipeptide analogs (Figure 67). The adopted synthetic route for 255 and 256, depicted in Scheme 37, used resin bound H-Ser(OtBu) as a starting material.
Figure 67
Figure 67. Molecular structures of amylin (20–29) 254 and its modified bioisosteric analogs.
Scheme 37
Scheme 37. Solid Phase Synthesis of an Alkene Dipeptide (255) and Alkene Dipeptidosulfonamide Isostere (256)
Both compounds were characterized by electrospray mass spectrometry. Rapid gel formation, which was used to measure aggregation behavior, indicated that 255 and 256 decrease gel formation time by 30 and 60 min, respectively, compared to parent amylin (<10 min). Compared to 254, both 255 and 256 displayed a significantly low number of amyloid fibrils in the transmission electron microscopy images. This retardation in fibril formation by both bioisosteres could be due to a lack of hydrogen bonding capabilities in the peptide backbone. Fourier transform infrared spectra (FTIR) and circular dichroism (CD) studies also validated that the modified dipeptide peptidomimetics exhibited superior activity in the retardation of fibril formation and altered β-sheet secondary structures when compared to the parent, 254.
Another instance of application of amide bond replacement and amide bioisosterism is seen in Yamamoto et al. studies to find an efficient DNA minor groove binding agent where the group synthesized distamycin related structural analogs.(272) Distamycin (262) is a naturally occurring tripeptide antibiotic that binds to the nonintercalative minor groove of DNA, with high selectivity toward AT-rich sequences.(273) The structural modification of the parent compound 262 at the distal C-terminal, by replacing the amidine group with a dimethylamino group, yielded compound 263, and further alteration at the N-terminal in 263 yielded 264, which had a nitro group. Compounds 263 and 264 were altered so as not to contain any amide bioisostere. One of the inter-pyrrole linkers (amide bond) of 264 was replaced by a trans-olefin to produce compound 265 to determine the effect of amide bond replacement or amide bioisosterism on its DNA binding properties (Figure 68).
Figure 68
Figure 68. Distamycin (262) and its bioisosteric analogs.
The general synthetic route to access compound 265 is shown in Scheme 35, ii. The results of the ethidium displacement assay indicated that the modified compounds 263, 264, and 265 had a lower DNA binding affinity for poly(dA-dT) compared to 262. However, the replacement of the amide bond with a trans olefin, as in compound 265, produced the highest DNA binding for poly(dG-dC); Kapp = 7.4 × 105 M–1 compared with 262, 263, and 264. Overall, the structural modification related to amide function could produce compounds that may have different DNA recognition patterns.
An interesting observation regarding the effect of replacing a peptide bond with an E-alkene is provided by the bombesin receptor antagonist 268, derived from compound 266, with speculation that the E-alkene bond could provide high lipophilicity and enhanced resistance to biodegradation.(274) The biological results were compared to a short chain pseudopeptide 267, which is also a bombesin analog. Both peptides 267 ([d-Phe6,Leu13Ψ(CH2NH)Leu14]bombesin(6–14)) and 268 ([d-Phe6,Leu13Ψ[(E)-CH═CH]Leu14]bombesin(6–14)) have similar structures except that 268 has a E-alkene bond inserted between the 13th and 14th position in bombesin (see cross-reference for synthetic procedure) (Figure 69).
Figure 69
Figure 69. Amino acid sequences of bombesin (266), pseudopeptide 267, and E-alkene isostere 268.
The antagonistic activity of 268 for the bombesin receptor was 10 times greater than 267 in terms of its inhibition of bombesin-stimulated amylase release in rat pancreatic acini. Furthermore, additional pharmacological experiments revealed that 268 efficiently blocked bombesin-stimulated amylase release; however, 267, even at the highest concentration used, failed to completely block amylase release, indicating that compound 268 is a very potent and specific bombesin antagonist in rat pancreatic acini that could be a useful probe for studying the biological actions of bombesin and its related peptides.
Another example of an E-olefin bioisostere as an amide bond replacement are the mutants of Aβ(1–40) Phe19-Phe20 which inhibit amyloid Aβ peptide amyloidogenesis and have been implicated in the formation of many distinct quaternary structures involved in the pathogenesis of AD.(275−277) The Aβ fibril structure is stabilized by various inter- and intramolecular hydrophobic interactions, salt bridges, and intermolecular hydrogen bonds. Therefore, interrupting intermolecular backbone–backbone hydrogen bonding in one of the hydrophobic subsequences, i.e., LVFFA (17–21) in Aβ(1–40), could prevent many peptides from forming cross-β-sheets-based amyloid fibrils. Subsequently, Kelly et al. in 2005 substituted a trans alkene moiety for an amide in the key Phe19-Phe20 subsequence, thereby eliminating a hydrogen bond donor and acceptor from the desired site (Figure 70).
Figure 70
Figure 70. Graphical representation of the modification of peptide backbone from an amide to E-olefin, which is neither a hydrogen bond donor nor acceptor.
Initially, the stereoselective E-olefin dipeptide isostere (270) was synthesized according to the general synthetic method shown in Scheme 36, ii, and then incorporated into the Aβ(1–40) peptide in place of phenylalanine 19 and 20 (abbreviated as Phe19-Phe20) by solid phase peptide synthesis using hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) activation. The final Phe19-Phe20 E-olefin analog of Aβ(1–40) was referred to as EOAβ, and its efficacy to inhibit fibrillar aggregation into protofilaments and fibrils having a cross β-sheet structure was confirmed by circular dichroism and atomic force microscopy (AFM) methods.(278)
Researchers at the Neuroscience Research Pharmaceutical Product Division of Abbott Laboratories, prepared E-alkene bioisosteres of the amide bond in cholecystokinin (CCK) peptides, with the aim of developing potent and selective cholecystokinin brain (CCK-B) ligands.(279) The systematic replacement of the amide linkage via an E-alkene was done to mimic the size, geometry, bond angle, and bond length of the amide. While the amide bond undergoes restricted rotation, it does still rotate, which is important for hydrogen bonding at the receptor binding site. In contrast, the E-alkene cannot form hydrogen bonds, and thus, the amide linkages at different positions of CCK peptides were replaced by an E-alkene and tested to determine if they were bioactive. This modification strategy was used as it was postulated that it would provide important information about the role of each amide bond in the CCK peptide. Among six pseudopeptides synthesized, the potency and functional activity of the 273 (Boc-Leu[E-CH═CH]Gly-Trp-Leu-Asp-PheNH2) isostere was similar to that of the parent peptides, Boc-protected CCK-6 hexapeptide (Boc-Leu-Gly-Trp-Leu-Asp-PheNH2; 272) and Boc-protected (CCK-4) tetrapeptide (Boc-Trp-Met-Asp-PheNH2; 271) (Figure 71).
Figure 71
Figure 71. Bioisosteric replacement of amide linkages from parent CCK peptides 271 and 272 to develop E-alkene isostere 273, a potent CCK-B receptor ligand.
The target peptide, 273, was synthesized by incorporating an E-alkene dipeptide isostere (i.e., Boc-LeuΨ[E-CH═CH]Gly-OH) and a CCK residue using a standard peptide coupling procedure (Scheme 38). Overall, the results of this study indicated that the bioisosteric replacement of an amide bond at the Leu-Gly region of CCK-6 is acceptable for retaining the bioactive conformation required for receptor activation.(279)
Scheme 38
Scheme 38. Synthetic Route Showing the Peptide Coupling of the Dipeptide Isostere with CCK Fragment To Obtain Target Pseudopeptide 273
Fluoroalkene Bioisosteres
ARTICLE SECTIONS
Fluoroalkene, also known as monofluoroalkene, has generated interest as a surrogate of the amide functional group. Geometrically, both the amide and fluoroalkene are similar; for example, the length of the C═O bond of the amide is 1.228 Å and the C–N bond is 1.368 Å, whereas the C–F bond is 1.376 Å and C═C bond is 1.333 Å. Furthermore, the fluorine atom mimics the oxygen atom of the carbonyl to a certain extent because both have similar van der Waals radii (1.47 Å for fluorine and 1.52 Å for oxygen).(280) The double bond of the fluoroalkene imparts rigidity to the molecule. The high electronegative fluorine atom mimics the carbonyl oxygen of the amide and thus provides fluoroalkene with a dipole moment of 1.4 D (3.6 D in the case of an amide). Finally, the fluoroalkene isostere could serve as a weak hydrogen bond acceptor to make either intermolecular or intramolecular hydrogen bonds. Furthermore, the (Z)-fluoroalkene mimics the s-trans amide bond, whereas the (E)-fluoroalkene mimics the s-cis form, and it could be explained because no equilibrium exists between them. Also, the fluoroalkene moiety is more lipophilic than an amide and therefore could be potentially used as a metabolically stable amide bioisostere.(280) In this context, several investigators have shown that the replacement of an amide bond with the fluoroalkene moiety produced superior metabolic stability, lipophilicity, and binding selectivity.
The search for a selective DOPr agonist is of interest for the development of novel medications to treat chronic pain, inflammation, and cancer pain. Compound 238 (Tyr1-Gly2-Gly3-Phe4-Leu5) is a pentapeptide that is an endogenous ligand for the δ opioid receptor, but its therapeutic application is limited due to its extremely poor selectivity with respect to the μ opioid receptor and hydrophilic character.(281) Also, the in vivo administration of 238 is problematic due to poor PK properties, including the rapid cleavage of Tyr1-Gly2 by aminopeptidase N in human plasma (t1/2 = 0.69 min) and Gly3-Phe4 by the angiotensin-converting enzyme present in the blood–brain barrier.(282,283) To improve these pharmacological attributes of 238, Altman and colleagues tactfully replaced the amide linkage of the Tyr1-Gly2 with a fluoroalkene (275) and trifluoroethylamine moiety to yield compounds (S)-276 and (R)-277, respectively (Figure 72).(284,285) The key synthetic steps to generate a fluoroalkene isostere in compound 275 are shown in Scheme 39.
Figure 72
Figure 72. Bioisosteric replacement of an amide bond at the Tyr1-Gly2 position in 238 with a fluoroalkene to produce 275 and a trifluoroethylamine moiety to produce (S)-276 and (R)-277.
Scheme 39
Scheme 39. Synthetic Route To Access Leu-enkephalin Analog 275
The results indicated that compound 275 activated δ-receptors stably expressed in CHO cells (EC50 = 5 nM), whereas the progenitor 238 had a 60-fold higher activity (EC50 = 0.08 nM). However, 275 had a similar selectivity for μ versus δ as the parent peptide 238. Most importantly, 275 had excellent stability in both Sprague-Dawley rat (76% remaining of 275 at 4 h versus t1/2 < 5 min for 238) and human plasma (68% remaining of 275 at 4 h versus t1/2 < 12 min for 238) compared to 238. Furthermore, 275 had improved in vivo distribution in a BALB/c mouse model with 50 mg/kg intravenous dose and the plasma concentrations of 275 were detected for 2 h, whereas 238 was completely metabolized within 5 min. Also, 275 was orally bioavailable and plasma concentrations were detected up to 30 min after an oral dose of 400 mg/kg in the BALB/c mouse model.
These results suggested that 275 has significantly improved in vivo distribution (in both plasma and CNS), which was negligible for 238. This improvement of 275 over 238 could be explained by the σ-electron withdrawing effects of the fluorine atom, which decreased the basicity of the neighboring functional groups, making them less prone to hydrogen bond with H2O, as well as the catalytic domains of the metabolizing enzymes. Neither (S)-276 nor (R)-277 were active at δ or μ receptors and therefore were not assessed for stability, metabolism, and distribution.
In another study by a different research group, the bioisosteric replacement of the Gly3-Phe4 amide bond was conducted by Nadon et al.(286) Previously, these authors systematically replaced the Gly3-Phe4 amide linkage with a thioamide (Ki = 47 ± 17 nM)(287) and ester bioisostere (Ki= 34 ± 17 nM) (Figure 73).(260) These isosteres retained δ-opioid receptor activity, which suggested that a hydrogen bond donor at this site of 238 was not essential, and this led to the design of a fluoroalkene bioisostere (283). This compound was obtained by first synthesizing fmoc-protected benzyl fluoropentenoic acid intermediate (286) which was later used in solid-phase synthesis (SPPS) utilizing 2-chlorotrityl chloride resin (CTS). The synthetic route of 283 is shown in Scheme 40.
Figure 73
Figure 73. Structures of the parent peptide 238 and its fluoroalkene isostere 283.
Scheme 40
Scheme 40. Synthetic Pathway To Obtain the Fluoroalkene Peptidomimetic Compound 283
The δ-opioid receptor binding affinity of 238 and 283 was calculated by competitive binding assays using iodinated deltorphin I ([125I]-deltorphin I) in membrane preparations obtained from HEK293 cells expressing a FLAG-tagged version of the mouse δ-opioid receptor. The results indicated that 283 had a high affinity for δ-opioid receptor (Ki = 43 ± 14 nM), although its affinity was lower than the parent peptide 238 (Ki = 6.9 ± 2.3 nM) (Figure 73). However, its affinity for the δ-opioid receptor was significantly greater than the trans-alkene isostere (Ki = 587 ± 19 nM).(288) This weak activity of the trans-alkene isostere highlighted the significant role of the fluorine atom as an effective functional mimicry of the hydrogen bond accepting feature of the amide.
Daclatasvir (formerly known as BMS-790052) (290) (Figure 74) is a small molecule inhibitor of HCV NS5A that has potent in vitro anti-HCV efficacy in the picomolar range in HCV replicons from various genotypes.(289) In order to obtain an improved structural understanding of this chemotype template for designing novel NS5A inhibitors, Chang and co-workers synthesized fluoro-olefin-based structures, as they hypothesized they may provide a new peptidomimetic approach for developing potent and structurally unique inhibitors of HCV NS5A.(290) The intermolecular hydrogen bonded amide group in 290 was successfully replaced with a fluoro-olefin motif to obtain compound 291, and the synthetic route is depicted in Scheme 41.
Figure 74
Figure 74. Bioisosteric replacement of the amide function in daclatasvir, 290, with a fluoro-olefin moiety to yield 291.
Scheme 41
Scheme 41. Diastereoselective Synthesis of Fluoro-olefin Analog 291 by Chang and Co-workers
The anti-HCV efficacy was measured in a clone A replicon whole cell assay, and the results indicated that 291 inhibited HCV genotype 1b replication in the picomolar range (EC50 = 79 pM), similar to the parent peptide 290 (Figure 74). Furthermore, the computational modeling studies indicated that this fluoro-olefin isostere favored a γ-turn substructure which is necessary for the interaction with the NS5A protein. Finally, 291 did not have any cytotoxicity up to the highest concentration tested (CC50 > 10 μM).
Miscellaneous Amide Bioisosteres
ARTICLE SECTIONS
The signaling of RhoaA/C is important for metastases and invasion of several cancers. Knockout and siRNA data have revealed an important in vivo role for RhoC in breast cancer metastasis as well as for megakaryoblastic leukemia transcriptional coactivator proteins (MKL1) and serum response factor (SRF) in breast and cancer metastases. These results reveal that Rho signaling and, more specifically, Rho-regulated gene transcription can be targets for cancer.(291) Evelyn and colleagues identified compound 301 (Figure 75), which blocks SRE-luciferase gene transcription when RhoA and RhoC signaling pathways are activated. Compound 301 potently inhibited LPA-induced DNA synthesis in PC-3 cells (<1 μM). Additionally, it inhibited the growth of RhoC-overexpressing melanoma cells at nanomolar concentrations but was less active in cell lines expressing lower levels of RhoC. Compound 301 inhibited spontaneous PC-3 prostate cancer cell Rho-dependent invasion through a Matrigel matrix but failed to do so in vitro in a Gαi-dependent lysophosphatidic acid (LPA-stimulated) SKOV-3 ovarian cancer cell invasion model. On the basis of these favorable results on cancer cell function, it was decided that 301 would be a promising lead. Compound 301 also showed acute cellular toxicity toward PC-3 cells at 24 h and consequently decrease in cell viability.
Figure 75
Figure 75. Inhibitor of Rho/MLK1 transcriptional pathway 301 and analogs with amide bioisosteric replacements 302 and 303.
Therefore, the next goal was to make modifications in this initial lead to improve potency and or selectivity while diminishing its cytotoxicity. The three areas of concern from this initial lead were the nitrogen–oxygen bond between the two carboxamides being susceptible to cleavage by thiols, the two carboxamides limiting potency and interfering with cell penetration, and the two aromatic rings not being optimal motifs for potency and selectivity. The initial strategy to modify these areas included removing the nitrogen–oxygen bond and employing a bioisosteric replacement of the amides, and conformational restriction imposed between the two aromatic rings. Making changes on the tether between the two carboxamides of 301 was first evaluated. Results indicated that removing the methyl group led to little effect on activity or selectivity. Replacing the oxygen atom with a carbon atom eliminated acute toxicity even at higher doses. Next, modifications were made on the secondary amides. When the hydrogen bond donor was removed to improve cell permeability, this gave rise to a dramatic loss in activity. When the anilides were replaced, it had a detrimental effect, but reducing the amides to amines was more successful. A monoamine (303) (Figure 75) retained moderate selectivity with little cytotoxicity compared to another monoamine and diamine analogs. The bioisosteric replacement of the amide with triazoles, thiazole, and oxazole led to completely inactive compounds indicating “traditional” heterocylic amide bioisosteres would be ineffective.
Several analogs were tested for their ability to inhibit PC-3 prostate cancer cell invasion in a Matrigel matrix (% inhibition invasion at 10 and 100 μM) as well as their ability to inhibit mitochondrial metabolism when using WST-1 (% inhibition WST-1 at 10 and 100 μM) in comparison to 301 (Figure 75). All conformationally restricted analogs had equivalent efficacies against SRE.L at 10 and 100 μM and had similar activity in a Matrigel assay. Compound 302 was slightly less toxic at 100 μM (23%) with an efficacy:toxicity profile at 100 μM higher than that of 301 (Figure 75). The monoamine bioisostere 305 was synthesized by alkylation of 4-chloroaniline with 3-bromopropylamine which led to compound 303 over several steps (Scheme 42). Compound 303 had the best efficacy:cytotoxicity ratio in transfected cell SRE-luciferase studies. Additionally, it inhibits invasion at 10 μM (54%), similar to that of 301 (71%), with no apparent toxicity. At 100 μM concentration, there is almost complete inhibition of invasion (84%) with less toxicity (27%) compared to 301 at 10 μM (54%). Overall the nipecotic amide 302 and monamine 303 were able to inhibit Gα12QL-stimulated SRE.L-luciferase expression with efficacy equal to 301 but with reduced cytotoxicity. These studies revealed the correlation between inhibition of Rho-mediated gene expression to cell invasion in a Matrigel matrix model of metastasis.(291)
Scheme 42
Scheme 42. Synthetic Access To Amide Bioisostere Analog 303 of a Rho/MLK1 Transcriptional Pathway Inhibitor 301
A thiophenecarboxylic acid series is one of several chemical classes that has been reported to inhibit the function of NS5B in genotype la and lb HCV at an allosteric thumb site near the active site.(292) Exploration of this series began with 3-arylsulfonamidothiophene-2-carboxylic acids and then proceeded to the application of aromatic and heteroaromatic amide isostere analogs. The problem with these amide bioisosteres was that they resulted in weaker enzyme inhibitors with reduced cellular potency. Therefore, Canales and colleagues turned to other structural motifs in order to identify novel NS5B inhibitors of the thiophenecarboxylic acid series.(292) They decided to use substituted N-acylhydrazines as tertiary amide replacements. Similar to amides, N-acylhydrazines are conformationally restricted due to resonance between the α-nitrogen and the carbonyl. As a result, trisubstituted N-acylhydrazines were synthesized, and a direct hydrazine analog (compound 307) of the protypical amide 306 (IC50 = 0.086 μM) (Figure 76) led to a compound with similar NS5B inhibitory potency (IC50 = 0.088 μM). A cocrystal structure of this direct hydrazine analog bound to NS5B proved the conformational similarity of the N-acylhydrazine to the amide. Additionally, the physiochemical properties were not significantly changed with the N-acylhydrazine replacement. It was then determined that the N-acylhydrazine was a reasonable tertiary amide bioisostere, thus resulting in the evaluation of a range of Nβ substituents having increased steric bulk to further rigidify the orthogonal conformation along with adding polar substituents in order to engage the solvent-exposed region next to the binding pocket. Linear and cyclic alcohols resulted in similar binding affinities to that of 306. Nonaromatic heterocycles gave rise to excellent binding affinities; however, inhibition of enzymatic activity was lower for these analogs in comparison to 306. The synthetic method for a 4-Me-piperidinyl analog 308 is shown in Scheme 43. In vitro evaluation of compound 308 (IC50 = 0.063 μM) (Figure 76) showed significant improvement in cellular activity for both genotypes. This study showed that trisubstituted acylhydrazines could serve as tertiary amide bioisosteres.
Figure 76
Figure 76. Trisubstituted acylhydrazine as a tertiary amide bioisostere.
Scheme 43
Scheme 43. Synthetic Route To Access 308, a HCV NS5B Thumb Site II Inhibitor
Conclusion
ARTICLE SECTIONS
The amide bond, beyond its critical function in protein structures, is most often encountered in hit, lead, and candidate compounds for therapeutic discovery across a wide range of disease indications. The resonance structure of the amide group gives way to restricted configuration engendering trans geometry of substituents, hydrogen bond accepting ability of the oxygen but not the nitrogen atom and hydrogen bond donating ability (if the nitrogen is not trisubstituted). These collective features provide for the often-critical role the amide plays in the pharmacophore or auxophore of bioactive compounds, providing either target binding interactions, positioning of bioactive configuration, or both. Successful bioisosteres of the amide bond are required to closely mimic these features while overcoming the Achilles heel of the group: its metabolic lability. Thus, amide bioisosteres tend to see employment in lead compound optimization to improve absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties.
Bioisosteres, by nature of their differing size, shape, and hydrogen bond donating and accepting profile, can convey additional target binding interactions to enhance (or degrade) activity depending on the interactions the amide bond makes with the target protein. However, this is often seen in combination with extensive SAR studies guided by in silico approaches that is often not directly attributed to the bioisostere itself but more a combination of differing substituents in differing configuration. While many potential bioisosteres of the amide group have been evaluated, there are a select few, summarized herein (Table 2), that provide a blend of similar hydrogen bonding pattern, restricted rotation, lipophilicity, and metabolic stability. For example, the ethane moiety has been employed as a bioisostere of the amide group that provides for significant metabolic stability but fails to mimic the hydrogen bonding, configurational, and hydrophilic character of the amide. Thus, ethane’s use is limited to compounds wherein the amide is not present in the pharmacophore or auxophore. The ability of amide bioisosteres to confer additional properties beyond PK/PD modulation, such as engendering blood–brain barrier penetration, has been reported (see methylamide 240 as an example), although it is worth noting that this is not an inherent property of any bioisostere to date but more a design feature to remove penetration hindering molecular features of the amide bond, such as hydrogen bond donors and charged acids generated by metabolic cleavage, or simply to increase lipophilicity, three strategies widely employed in CNS drug discovery.(293)
a
Footnotes: 1Improvements to potency and selectivity are generally excluded as they are most likely due to additional substituent modifications and/or increased target binding and cannot necessarily be attributed to the bioisostere alone. 2Comparisons are provided for compounds with the same or very similar substituents to the bioisostere where possible.
Novel bioisoteres continue to be developed with new heterocyclic rings and inorganic elements being investigated for their suitability as amide bioisosteres. The aminooxetane moiety, wherein the amine is bound directly to the heterocycle, imparts increased metabolic and chemical stability to peptidomimetic derivatives; however, the impact of this novel bioisostere on biological activity remains to be fully elucidated.(296,297) The loss of the rigidity of the amide bond and the increased separation of the oxygen from the backbone structure may have critical roles to play in retaining activity. Additionally, the oxetane ring has been utilized as a bioisostere for the methylene and gem-dimethyl groups(16) and carboxylic acids,(298) which may complicate its effects as a bioisostere for the amide group. The synthesis of oxetane-containing diketopiperazine bioisosteres, wherein the oxetane (or an azetidine) ring replaces the constrained amide carbonyl constituent, thus affording a spirocyclic system and combining the beneficial effects of two amide bioisosteres to maximize metabolic protection, has been reported.(299) However, no biological activity associated with these structures has been published to the best of our knowledge, making the suitability of this spirocycle as a bioisostere of the amide bond unclear. In both cases the ability of the oxetane ring to introduce three-dimensionality over the two-dimensionality of a carbonyl benefits in moving away from planar “drug-like” structures and into more novel chemical space.(300)
Boron-containing structures continue to gain traction in medicinal chemistry.(301,302) The boronamide structure B(OH)-NH is a theoretical bioisostere for the amide moiety. Initial modeling studies of energy barriers to rotation performed on N-methyl methylboronamide illustrate the double bond character of the boron–nitrogen bond and single bond character of the B–O bond mimicking the natural amide bond.(303) However, given synthetic challenges in accessing this particular functional group with the desired variety of substituents, the theory, to the best of our knowledge, has not been reduced to practice.
Silicon is gaining attention in medicinal chemistry for the role it can play in expanding chemical space.(304) The reported use of silanols to mimic the transition state of protease inhibitors(305) and to act as a biosiostere of terminal N-(hydroxy)amides in histone deacetylases (HDAC) inhibitors (albeit with reduced activity)(306) is pointing the way for the direct investigation of silanols as amide bioisosteres. The pioneering work of Chris McGuigan in the development of phosphonamidate protide technology(307) has led to a large amount of literature on the synthesis and biological stability of these moieties. These data can perhaps be mined to discover potential improvements on the traditional C–P bond-containing phosphonamidite bioisostere described above or to introduce the phosphonamidate moiety as an amide bioisostere itself, albeit with intracellular metabolic lability.
These few selected examples provide a glimpse of emerging novel amide bioisosteres that are under evaluation for adding to the medicinal chemist’s toolbox. The examples illustrated in this Perspective were chosen to highlight the power of amide bond bioisosteres in hit-to-lead and lead optimization to preserve, or enhance, activity and selectivity and to enhance PK/PD properties. Included are many examples of clinical candidates and clinically approved drugs reflecting the importance of this approach to drug discovery.
The authors declare no competing financial interest.
Author Information
ARTICLE SECTIONS
- Paul C. Trippier - Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States; UNMC Center for Drug Discovery, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States;
http://orcid.org/0000-0002-4947-5782;
The authors declare no competing financial interest.
Biographies
ARTICLE SECTIONS
Shikha Kumari
Shikha Kumari received her B.S. from the University of Delhi, India, and perused an M.S. in Pharmaceutical Chemistry from Banasthali University, India. In 2016, she received her Ph.D. in Biomedical Sciences from ACBR, University of Delhi, India, and worked in the area of medicinal chemistry that includes design, synthesis, and development of novel heterocyclic compounds against neurological disorders and cancer. She carried out her postdoctoral research work (2016–2018) in Dr. Manisha Tiwari’s (ACBR, University of Delhi) and Professor Nasimul Hoda’s laboratories (Jamia Millia Islamia, India). In 2019, she joined Dr. Paul C. Trippier’s lab at the University of Nebraska Medical Center as a postdoctoral member and is working on the development of novel treatments for ischemic stroke and cancer.
Angelica V. Carmona
Angelica V. Carmona obtained her B.S. in Biochemistry from Mount Saint Mary’s University Los Angeles, CA, U.S.. In 2018, she joined Dr. Paul C. Trippier’s lab at Texas Tech University Health Sciences Center and in 2019 moved to the University of Nebraska Medical Center as a Ph.D. scholar. Her current research work focuses on synthesizing novel neuroprotective compounds as potential therapeutics for the treatment of the rare pediatric disorder Batten disease.
Amit K. Tiwari
Amit K. Tiwari obtained his B.Pharm. from the Ram-Eesh Institute of Technology, India. He received his M.S. and Ph.D. in Pharmaceutical Sciences from the St. John’s University, Queens, NY (2008 and 2011, respectively). He then carried out postdoctoral research in Professor James Gallo’s laboratory at Icahn School of Medicine (2011–2013) in the area of pharmacokinetics. He joined Tuskegee University as an Assistant Professor prior to joining the Department of Pharmacology and Experimental Therapeutics at the University of Toledo, Ohio, as an Assistant Professor in 2015. In 2019, he was promoted to Associate Professor with tenure. His research interests are in broad areas of cancer pharmacology, drug development, and medicinal chemistry.
Paul C. Trippier
Paul. C. Trippier gained his M.Chem. from the University of Hull (U.K.) and his D.Phil. in Synthetic Organic Chemistry from the University of Oxford under the mentorship of Professor Mark Moloney. After postdoctoral positions with Prof. Chris McGuigan (Cardiff University) and Prof. Richard Silverman (Northwestern University) he began his independent career at Texas Tech University Health Sciences Center where he was promoted to Associate Professor with tenure. In 2019, he moved to the College of Pharmacy at the University of Nebraska Medical Center where his research group investigates small molecule probe and drug discovery for cancer, ischemic stroke, and neurodegenerative diseases among other indications.
Acknowledgments
ARTICLE SECTIONS
We thank the National Cancer Institute of the National Institutes of Health under Award R01CA226436 and the National Institute for Neurological Disorders and Stroke of the National Institutes of Health under Award R01NS106879 and the University of Nebraska Medical Center for funding support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
| Abbreviations Used | |
| Αβ | amyloid-β |
| A2A | adenosine A2A |
| Α549 | human lung cancer |
| ACAT | A:cholesterol acyltransferase |
| ACE | angiotensin-converting enzyme |
| ADMET | absorption, distribution, metabolism, excretion, and toxicity |
| AD | Alzheimer’s disease |
| AFC | N-acetyl-S-farnesyl-l-cysteine |
| AFM | atomic force microscopy |
| AIDS | acquired immune deficiency syndrome |
| AKR1C3 | aldo–keto reductase 1C3 |
| AML | acute myeloid leukemia |
| AMFC | amide modified farnesyl cysteine analog |
| ATP | adenosine triphosphate |
| BBB | blood–brain barrier |
| B16F10 | Mus musculus skin melanoma cells |
| BACE-1 | β-site amyloid precursor protein cleaving enzyme 1 |
| BAEC | bovine aortic endothelial cell |
| BCC | basal-cell carcinoma |
| Bcr-Abl | break point cluster region Abelson kinase |
| Caki-2 | human renal cancer |
| CB | cannabinoid |
| CB1 | cannabinoid-1 |
| CB2 | cannabinoid-2 |
| CCK | cholecystokinin |
| CCK-B | cholecystokinin brain |
| CD | circular dichroism |
| Cat K | cathepsin K |
| CDI | carbonyldiimidazole |
| CEM | human T-lymphocyte cell |
| CGRP | calcitonin gene related peptide |
| CHO | Chinese hamster ovary |
| CIDV | capsaicin induced dermal vasodilation |
| CML | chronic myelogenous leukemia |
| CuAAC | copper(I)-catalyzed azide–alkyne cycloaddition |
| CuI | copper iodide |
| CNS | central nervous system |
| CRL-8155 | human lymphoblast cell |
| CRPC | castration-resistant prostate cancer |
| CTC | 2-chlorotrityl chloride resin |
| CyP | liver cytochrome |
| D2-R | dopamine-2 subtype receptor |
| D3-R | dopamine-3 subtype receptor |
| DGAT | acyl CoA:diacylglycerol acyltransferase |
| DKP | diketopiperazine |
| DOPr | δ opioid receptor |
| DPP-4 | dipeptidyl peptidase-4 |
| DIAD | diisopropyl azodicarboxylate |
| DSG | 15-deoxyspergualin |
| EDG | electron donating group |
| ERK1/2 | extracellular signal-regulated kinases 1 and 2 |
| EWG | electron withdrawing group |
| FDA | Federal Drug Administration |
| FTIR | Fourier transform infrared |
| GABAA | γ-aminobutyric acid A |
| GPCR | G-protein-coupled receptor |
| GIST | gastrointestinal stomatal tumor |
| GLP-1 | glucagon-like peptide 1 |
| GIP | glucose-dependent insulinotropic polypeptide |
| Gpp(NH)p | 5′-guanylyl imidodiphosphate |
| GSH | glutathione |
| GT1 | genotype 1 |
| GTL-16 | human gastric carcinoma |
| GVHD | graft-versus-host disease |
| h | human or hour |
| HATU | hexafluorophosphate azabenzotriazole tetramethyluranium |
| hCB1 | human cannabinoid 1 |
| H1437 | non-small-cell lung cancer |
| HAT | human African trypanosomiasis |
| HBA | hydrogen bond acceptor |
| HBD | hydrogen bond donor |
| HCV | hepatitis C virus |
| HCMV | human cytomegalovirus |
| HD | Huntington’s disease |
| HDAC | histone deacetylase |
| HGF | hepatocyte growth factor |
| Hh | Hedgehog |
| hIcmt | human isoprenylcysteine carboxyl methyltransferase |
| HeLa | human cervix carcinoma |
| hERG | human ether-a-go-go-related gene |
| HEK293 | human embryonic kidney 293 |
| HepG2 | human liver cancer |
| HINF | Haemophilus influenzae 30063 |
| HIV | human immunodeficiency virus infection |
| HMEC-1 | human microvascular endothelial cells |
| HL-60 | human leukemia |
| HLM | human liver microsome |
| HT22 | mouse hippocampal neuron |
| HT-29 | human colon cancer |
| 5-HT | 5-hydroxytryptamine |
| HUVEC | human umbilical vein endothelial cell |
| Icmt | isoprenylcysteine carboxyl methyltransferase |
| ip | intraperitoneal |
| iv | intravenous |
| IL-12 | interleukin 12 |
| IL-17 | interleukin 17 |
| IL-23 | interleukin 23 |
| INSTI | integrase strand transfer inhibitor |
| JAK | Janus kinase |
| KOPr | κ opioid receptor |
| LA | α-lipoic acid |
| L1210 | murine leukemia cell |
| m | mouse |
| MCF10A | human mammary epithelial cell |
| mGlu7-NAM | metabotropic glutamate receptor subtype-7 negative allosteric modulator |
| MDCK | Madin–Darby canine kidney |
| MDA-MB-231 | M. D. Anderson metastasis breast adenocarcinoma |
| Met | N-methyl-N′-nitrosoguanidine human osteosarcoma transforming gene |
| MIC | minimal inhibitory concentration |
| MKL1 | megakaryoblastic leukemia transcriptional coactivator protein |
| MLM | mouse liver microsome |
| MMP | matrix metalloproteinase |
| MOPr | μ opioid receptor |
| MT4 | human T-lymphoid cell |
| MTR | melatonin receptor |
| MT1R | melatonin receptor 1 |
| MT2R | melatonin receptor 2 |
| MW | microwave |
| nAChR | neuronal nicotinic acetylcholine receptor |
| NADPH | nicotinamide adenine dinucleotide phosphate |
| NDA | new drug application |
| NEP | metalloproteinase neutral endopeptidase |
| NET | neutrophil extracellular trap |
| NK-1 | neurokinin-1 |
| NPA | [3H]spiro-peridol/N-propylnorapomorphine |
| NS5B | nonstructural protein 5B |
| NSAID | nonsteroidal anti-inflammatory drug |
| ORTEP | Oak Ridge thermal ellipsoid plot |
| PAD | protein arginine deiminase |
| PAF | platelet-activating factor |
| PC-3 | human prostate cancer |
| PD | pharmacodynamic |
| PD | Parkinson’s disease |
| PDHc | pyruvate dehydrogenase complex |
| PDHc-E1 | pyruvate dehydrogenase complex-E1component |
| PK | pharmacokinetic |
| PrCP | prolylcarboxypeptidase |
| po | per oral |
| PTM | post-translational modification |
| RdRp | RNA-dependent RNA polymerase |
| RTK | receptor tyrosine kinase |
| SAR | structure–activity relationship |
| SAUR | Staphylococcus aureus UC 9218 |
| SCD | stearoyl-CoA desaturase |
| SCD1 | stearoyl-CoA desaturase-1 |
| SEP1d | Staphylococcus epidermidis UC 12084 |
| SEPId | Staphylococcus epidermidis (UC 12084) |
| SMO | smoothened |
| SMFC | sulfonamide modified farnesylcysteine analog |
| SP | substance P |
| SRF | serum response factor |
| SPPS | solid-phase synthesis |
| STAT-5 | signal transducer and activator of transcription 5 |
| T-ALL | T-cell acute lymphoblastic leukemia |
| TBAF | tetrabutylammonium fluoride |
| TMSA | trimethylsilyl azide |
| tPSA | total polar surface area |
| TRPV1 | transient receptor potential cation channel subfamily V member 1 |
| TS | transition state |
| TYK2 | tyrosine kinase 2 |
| U2OS | PAD-4 expressing osteosarcoma bone marrow |
| VEGFR2 | vascular endothelial growth factor receptor-2 |
| VDA | vapor diffusion assay |
| VLA-4 | very late activating antigen-4 |
| Vif | viral infectivity factor |
References
ARTICLE SECTIONS
This article references 307 other publications.
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- 14Papadatos, G.; Brown, N. In silico applications of bioisosterism in contemporary medicinal chemistry practice. WIREs Comput. Mol. Sci. 2013, 3, 339– 354, DOI: 10.1002/wcms.1148[Crossref], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtV2ntrfN&md5=70c576ff3ad5c44f5b0394e6a4ef881bIn silico applications of bioisosterism in contemporary medicinal chemistry practicePapadatos, George; Brown, NathanWiley Interdisciplinary Reviews: Computational Molecular Science (2013), 3 (4), 339-354CODEN: WIRCAH; ISSN:1759-0884. (Wiley-Blackwell)A review. Bioisosterism is a key concept in medicinal chem., as it allows medicinal chemists to interchange structural fragments without significant perturbation in biol. activity. Not surprisingly, given the vast amt. of bioactivity data and chemoinformatics resources now available, there has been a significant surge in the no. of computational approaches available to mine and identify bioisosteric replacements for fragments of bioactive compds. Such methods have certainly provided medicinal chemists with a diverse arsenal of inhouse, com., and academic tools and interfaces to aid in the optimization across a no. of end points such as bioactivity; selectivity; and absorption, distribution, metab., excretion, and toxicity properties for effective and efficient drug design. These in silico bioisosteric replacement mining approaches can generally be divided into two categories, namely ligand based and structure based. The approaches of the former category use information that is derived from ligands, whereas the latter category requires knowledge of the biol. target, as well as specific knowledge of the interactions between ligand and target in the binding pocket. Ligand-based methodologies are also typically divided into similarity-based and database mining (or knowledge-based) approaches. In general, the former provide an assessment of putative bioisosteric fragments and substructures, in terms of mol. topol. and descriptors, whereas the latter ext. structural transformations from large chem. repositories and assoc. them with the induced change in biol. or any other property of interest. Following systematic retrospective studies, a large no. of nonclassical bioisosteric equiv. have been reported in the literature.
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- 17Meanwell, N. A. The Influence of Bioisosteres in Drug Design: Tactical Applications to Address Developability Problems. In Tactics in Contemporary Drug Design; Meanwell, N. A., Ed.; Springer: Berlin, 2015; pp 283– 381.
- 18Herr, R. J. 5-Substituted-1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methods. Bioorg. Med. Chem. 2002, 10, 3379– 3393, DOI: 10.1016/S0968-0896(02)00239-0[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xms12jurY%253D&md5=a7892c9a0eabe9a1b6c9ead0a3327a2e5-Substituted 1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methodsHerr, R. JasonBioorganic & Medicinal Chemistry (2002), 10 (11), 3379-3393CODEN: BMECEP; ISSN:0968-0896. (Elsevier Science Ltd.)A review on the medicinal chem. of tetrazolic acids highlighting some examples of tetrazole-contg. drug substances in the current literature. 5-Substituted 1H-tetrazoles (RCN4H) are often used as metab.-resistant isosteric replacements for carboxylic acids (RCO2H) in SAR-driven medicinal chem. analog syntheses. A survey of representative literature procedures for the prepn. of 5-substituted 1H-tetrazoles, focusing on prepns. from aryl and alkyl nitriles, is presented in sections by generalized synthetic methods.
- 19Bonandi, E.; Christodoulou, M. S.; Fumagalli, G.; Perdicchia, D.; Rastelli, G.; Passarella, D. The 1,2,3-triazole ring as a bioisostere in medicinal chemistry. Drug Discovery Today 2017, 22, 1572– 1581, DOI: 10.1016/j.drudis.2017.05.014[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFCmurrK&md5=0ea3588d22d266e5eed9f401c887b838The 1,2,3-triazole ring as a bioisostere in medicinal chemistryBonandi, Elisa; Christodoulou, Michael S.; Fumagalli, Gaia; Perdicchia, Dario; Rastelli, Giulio; Passarella, DanieleDrug Discovery Today (2017), 22 (10), 1572-1581CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)1,2,3-Triazole is a well-known scaffold that has a widespread occurrence in different compds. characterized by several bioactivities, such as antimicrobial, antiviral, and antitumor effects. Moreover, the structural features of 1,2,3-triazole enable it to mimic different functional groups, justifying its wide use as a bioisostere for the synthesis of new active mols. Here, we provide an overview of the 1,2,3-triazole ring as a bioisostere for the design of drug analogs, highlighting relevant recent examples.
- 20Lenci, E.; Trabocchi, A. Peptidomimetic toolbox for drug discovery. Chem. Soc. Rev. 2020, 49, 3262– 3277, DOI: 10.1039/D0CS00102C[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsFSnuro%253D&md5=6624d8fd44e8af567591e70815a649f6Peptidomimetic toolbox for drug discoveryLenci, Elena; Trabocchi, AndreaChemical Society Reviews (2020), 49 (11), 3262-3277CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. The art of transforming peptides into drug leads is still a dynamic and fertile field in medicinal chem. and drug discovery. Peptidomimetics can respond to peptide limitations by displaying higher metabolic stability, good bioavailability and enhanced receptor affinity and selectivity. Various synthetic strategies have been developed over the years in order to modulate the conformational flexibility and the peptide character of peptidomimetic compds. This tutorial review aims to outline useful tools towards peptidomimetic design, spanning from local modifications, global restrictions and the use of secondary structure mimetics. Selected successful examples of each approach are presented to document the relevance of peptidomimetics in drug discovery.
- 21Fosgerau, K.; Hoffmann, T. Peptide therapeutics: current status and future directions. Drug Discovery Today 2015, 20, 122– 128, DOI: 10.1016/j.drudis.2014.10.003[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsl2ksLnM&md5=f6b74aaa4e3fdb317b091b0450f3618aPeptide therapeutics: current status and future directionsFosgerau, Keld; Hoffmann, TorstenDrug Discovery Today (2015), 20 (1), 122-128CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. Peptides are recognized for being highly selective and efficacious and, at the same time, relatively safe and well tolerated. Consequently, there is an increased interest in peptides in pharmaceutical research and development (R&D), and approx. 140 peptide therapeutics are currently being evaluated in clin. trials. Given that the low-hanging fruits in the form of obvious peptide targets have already been picked, it has now become necessary to explore new routes beyond traditional peptide design. Examples of such approaches are multifunctional and cell penetrating peptides, as well as peptide drug conjugates. Here, we discuss the current status, strengths, and weaknesses of peptides as medicines and the emerging new opportunities in peptide drug design and development.
- 22Henninot, A.; Collins, J. C.; Nuss, J. M. The current state of peptide drug discovery: back to the future?. J. Med. Chem. 2018, 61, 1382– 1414, DOI: 10.1021/acs.jmedchem.7b00318[ACS Full Text], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1ansLbM&md5=825f15ed57fceaa1226f57be696c639eThe Current State of Peptide Drug Discovery: Back to the Future?Henninot, Antoine; Collins, James C.; Nuss, John M.Journal of Medicinal Chemistry (2018), 61 (4), 1382-1414CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Over the last decade, peptide drug discovery has experienced a revival of interest and scientific momentum, as the pharmaceutical industry has come to appreciate the role that peptide therapeutics can play in addressing unmet medical needs, and how this class of compds. can be an excellent complement or even preferable alternative to small mol. and biol. therapeutics. In this perspective we give a concise description of the recent progress in peptide drug discovery in a holistic manner, highlighting enabling technol. advances affecting nearly every aspect of this field: from lead discovery, to synthesis and optimization, to peptide drug delivery. An emphasis is placed on describing research efforts to overcome the inherent weaknesses of peptide drugs, in particular their poor pharmacokinetic properties, and how these efforts have been crit. to the discovery, design and subsequent development of novel therapeutics.
- 23Lau, J. L.; Dunn, M. K. Therapeutic peptides: historical perspectives, current development trends, and future directions. Bioorg. Med. Chem. 2018, 26, 2700– 2707, DOI: 10.1016/j.bmc.2017.06.052[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFygt7jP&md5=c4dc775ee302737cfc5080ea3f1c8c74Therapeutic peptides: Historical perspectives, current development trends, and future directionsLau, Jolene L.; Dunn, Michael K.Bioorganic & Medicinal Chemistry (2018), 26 (10), 2700-2707CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)A review. Peptide therapeutics have played a notable role in medical practice since the advent of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United States and other major markets, and peptides continue to enter clin. development at a steady pace. Peptide drug discovery has diversified beyond its traditional focus on endogenous human peptides to include a broader range of structures identified from other natural sources or through medicinal chem. efforts. The authors maintain a comprehensive dataset on peptides that have entered human clin. studies that includes over 150 peptides in active development today. Here the authors provide an overview of the peptide therapeutic landscape, including historical perspectives, mol. characteristics, regulatory benchmarks, and a therapeutic area breakdown.
- 24Lee, A. C.; Harris, J. L.; Khanna, K. K.; Hong, J. H. A comprehensive review on current advances in peptide drug development and design. Int. J. Mol. Sci. 2019, 20, 2383, DOI: 10.3390/ijms20102383[Crossref], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXosVGiuw%253D%253D&md5=344174f95cb22357d0b92d797874d81bA comprehensive review on current advances in peptide drug development and designLee, Andy Ch-Lung; Harris, Janelle Louise; Khanna, Kum Kum; Hong, Ji-HongInternational Journal of Molecular Sciences (2019), 20 (10), 2383/1-2383/21CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)Protein-protein interactions (PPIs) execute many fundamental cellular functions and have served as prime drug targets over the last two decades. Interfering intracellular PPIs with small mols. has been extremely difficult for larger or flat binding sites, as antibodies cannot cross the cell membrane to reach such target sites. In recent years, peptides smaller size and balance of conformational rigidity and flexibility have made them promising candidates for targeting challenging binding interfaces with satisfactory binding affinity and specificity. Deciphering and characterizing peptide-protein recognition mechanisms is thus central for the invention of peptide-based strategies to interfere with endogenous protein interactions, or improvement of the binding affinity and specificity of existing approaches. Importantly, a variety of computation-aided rational designs for peptide therapeutics have been developed, which aim to deliver comprehensive docking for peptide-protein interaction interfaces. Over 60 peptides have been approved and administrated globally in clinics. Despite this, advances in various docking models are only on the merge of making their contribution to peptide drug development. In this review, we provide (i) a holistic overview of peptide drug development and the fundamental technologies utilized to date, and (ii) an updated review on key developments of computational modeling of peptide-protein interactions (PepPIs) with an aim to assist exptl. biologists exploit suitable docking methods to advance peptide interfering strategies against PPIs.
- 25He, R.; Finan, B.; Mayer, J. P.; DiMarchi, R. D. Peptide conjugates with small molecules designed to enhance efficacy and safety. Molecules 2019, 24, 1855, DOI: 10.3390/molecules24101855[Crossref], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFagtb%252FM&md5=da04d398164460a08977abcdcefdc230Peptide conjugates with small molecules designed to enhance efficacy and safetyHe, Rongjun; Finan, Brian; Mayer, John P.; DiMarchi, Richard D.Molecules (2019), 24 (10), 1855CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. Peptides constitute mol. diversity with unique mol. mechanisms of action that are proven indispensable in the management of many human diseases, but of only a mere fraction relative to more traditional small mol.-based medicines. The integration of these two therapeutic modalities o ers the potential to enhance and broaden pharmacol. while minimizing dose-dependent toxicol. This review summarizes numerous advances in drug design, synthesis and development that provide direction for next-generation research endeavors in this field. Medicinal studies in this area have largely focused upon the application of peptides to selectively enhance small mol. cytotoxicity to more effectively treat multiple oncol. diseases. To a lesser and steadily emerging extent peptides are being therapeutically employed to complement and diversify the pharmacol. of small mol. drugs in diseases other than just cancer. No matter the disease, the purpose of the mol. integration remains const. and it is to achieve superior therapeutic outcomes with diminished adverse effects. We review linker technol. and conjugation chemistries that have enabled integrated and targeted pharmacol. with controlled release. Finally, we offer our perspective on opportunities and obstacles in the field.
- 26Kaspar, A. A.; Reichert, J. M. Future directions for peptide therapeutics development. Drug Discovery Today 2013, 18, 807– 817, DOI: 10.1016/j.drudis.2013.05.011[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpsV2ksbs%253D&md5=df04991ff869d0d85386254d378664ccFuture directions for peptide therapeutics developmentKaspar, Allan A.; Reichert, Janice M.Drug Discovery Today (2013), 18 (17-18), 807-817CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. The notable expansion of peptide therapeutics development in the late 1990s and the 2000s led to an unprecedented no. of marketing approvals in 2012 and has provided a robust pipeline that should deliver numerous approvals during the remainder of the 2010s. To document the current status of the pipeline, we collected data for peptide therapeutics in clin. studies and regulatory review, as well as those recently approved. In this Foundation review, we provide an overview of the pipeline, including therapeutic area and mol. targets, with a focus on glucagon-like peptide 1 receptor agonists. Areas for potential expansion, for example constrained peptides and peptide-drug conjugates, are profiled.
- 27Cramer, R. D.; Clark, R. D.; Patterson, D. E.; Ferguson, A. M. Bioisosterism as a molecular diversity descriptor: steric fields of single “topomeric” conformers. J. Med. Chem. 1996, 39, 3060– 3069, DOI: 10.1021/jm960291f[ACS Full Text], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xkt1alurw%253D&md5=599f03f9824679ca1ca4f762a1924e8dBioisosterism as a Molecular Diversity Descriptor: Steric Fields of Single "Topomeric" ConformersCramer, Richard D.; Clark, Robert D.; Patterson, David E.; Ferguson, Allan M.Journal of Medicinal Chemistry (1996), 39 (16), 3060-3069CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The comparative mol. field anal. steric field of a single "topomeric" conformer is introduced as a mol. diversity descriptor particularly useful for combinatorial chem. involving variations around a fixed "core". Using this new descriptor, 736 com. available thiols are divided into 231 bioisosteric clusters, whose compns. agree at least as well with medicinal chem. experience and intuition as do clusters derived from Tanimoto differences between 2D fragment occurrences. However, in practice topomeric steric fields complement 2D fingerprints, being the two most frequently useful descriptors yet found for neighborhood-based design of combinatorial libraries.
- 28Ertl, P. In silico identification of bioisosteric functional groups. Curr. Opin. Drug Discovery Dev. 2007, 10, 281– 288[PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmtVWlsrk%253D&md5=477b7ecaaf2a5323820f3b50c1559732In silico identification of bioisosteric functional groupsErtl, PeterCurrent Opinion in Drug Discovery & Development (2007), 10 (3), 281-288CODEN: CODDFF; ISSN:1367-6733. (Thomson Scientific)A review. Bioisosteric replacement is a std. technique that is used in medicinal chem. to design analogs of bioactive mols. with similar activity and with addnl. improved characteristics. However, successful bioisosteric design requires significant prior chem. knowledge, and the identification of a replacement group with an optimal balance of steric, hydrophobic, electronic and hydrogen-bonding properties that all influence ligand-receptor interactions usually requires a demanding procedure of trial and error. In this article, various methods that can help medicinal chemists to identify bioisosteric analogs are reviewed, beginning with classical techniques using exptl. group properties. Methods to find bioisosteric pairs based on the anal. of large mol. databases are discussed. Various descriptors to characterize properties of functional groups are described, and methods to identify bioisosteric replacement by conducting property similarity search are presented. Examples of tools that help chemists to navigate within the group functional property space are also provided.
- 29Devereux, M.; Popelier, P. L. A. In silico techniques for the identification of bioisosteric replacements for drug design. Curr. Top. Med. Chem. 2010, 10, 657– 668, DOI: 10.2174/156802610791111470[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlslSgsbo%253D&md5=86300aca3a8eebbe9df79c7a6c7be152In silico techniques for the identification of bioisosteric replacements for drug designDevereux, Mike; Popelier, Paul L. A.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10 (6), 657-668CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. This article provides an overview of the broad and increasingly varied selection of computational approaches available to find bioisosteric replacements for fragments of bioactive compds. The rapidly increasing no. and diversity of methods has provided medicinal chemists with a powerful range of com. and academic tools to aid in the optimization of lead compd. activity and ADMET properties for drug design. We discuss methods with fundamentally different philosophies, ranging from evaluation of similarity in a calcd. property space to cheminformatics anal. of pharmaceutical compd. databases. We also discuss the incorporation, within these methods, of a whole spectrum of exptl. and calcd. data to describe fragment chem. and compd. activity. Despite the growing sophistication of available techniques, there remains much scope for further development and esp. for deeper validation of the efficacy of different approaches in what seems set to remain an expanding field.
- 30Olesen, P. H. The use of bioisosteric groups in lead optimization. Curr. Opin. Drug Discovery Dev. 2001, 4, 471– 478[PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlsVKktbc%253D&md5=9798dc03c0dca889fcf94fe4fef7bb13The use of bioisosteric groups in lead optimizationOlesen, Preben H.Current Opinion in Drug Discovery & Development (2001), 4 (4), 471-478CODEN: CODDFF; ISSN:1367-6733. (PharmaPress Ltd.)A review with refs. It is now half a century since Friedman introduced the term bioisosterism for the similar biol. activity of structurally related compds. Since then, the concept has been used extensively and successfully in the optimization of lead compds. in drug discovery. The no. of chem. lead compds. has expanded enormously in recent years due to the expression of an increasing no. of recombinant proteins, and the screening of these new protein targets against a large no. of compds. in high-throughput screens. For the fine-tuning of lead compds. to obtain candidates suitable for clin. trials, which is in most circumstances still a tedious process, the use of bioisosteric replacement can be of significant value. This is esp. the case in optimizing for selectivity for a specific target and in improving the pharmacokinetic properties of lead compds. The use of bioisosteres in lead optimization is illustrated by some recent examples from the literature.
- 31Thornber, C. W. Isosterism and molecular modification in drug design. Chem. Soc. Rev. 1979, 8, 563– 580, DOI: 10.1039/cs9790800563[Crossref], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXktlKmsL0%253D&md5=25e8bd3c46affd25b72fbf87a44a3b27Isosterism and molecular modification in drug designThornber, C. W.Chemical Society Reviews (1979), 8 (4), 563-80CODEN: CSRVBR; ISSN:0306-0012.A review with 76 refs.
- 32Sun, S.; Jia, Q.; Zhang, Z. Applications of amide isosteres in medicinal chemistry. Bioorg. Med. Chem. Lett. 2019, 29, 2535– 2550, DOI: 10.1016/j.bmcl.2019.07.033[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFSrt7zE&md5=329e431db6b70c733130197e3828eb89Applications of amide isosteres in medicinal chemistrySun, Shaoyi; Jia, Qi; Zhang, ZaihuiBioorganic & Medicinal Chemistry Letters (2019), 29 (18), 2535-2550CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. Isosteric replacement of amide groups is a classic practice in medicinal chem. This digest highlights the applications of most commonly employed amide isosteres in drug design aiming at improving potency and selectivity, optimizing physicochem. and pharmacokinetic properties, eliminating or modifying toxicophores, as well as providing novel intellectual property of lead compds.
- 33Bachl, J.; Mayr, J.; Sayago, F. J.; Cativiela, C.; Díaz Díaz, D. Amide–triazole isosteric substitution for tuning self-assembly and incorporating new functions into soft supramolecular materials. Chem. Commun. 2015, 51, 5294– 5297, DOI: 10.1039/C4CC08593K[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitValurnF&md5=5827b04ade6463e7e5d061014e8d02f4Amide-triazole isosteric substitution for tuning self-assembly and incorporating new functions into soft supramolecular materialsBachl, Juergen; Mayr, Judith; Sayago, Francisco J.; Cativiela, Carlos; Diaz Diaz, DavidChemical Communications (Cambridge, United Kingdom) (2015), 51 (25), 5294-5297CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)The proof-of-concept for the modular synthesis of new functional soft gel materials based on amide-triazole isosteric replacement has been demonstrated. A coassembly approach of isosteric amino acid-based hydrogelators was fruitfully applied for fine-tuning the release of entrapped drugs.
- 34Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A. Click chemistry reactions in medicinal chemistry: applications of the 1,3-dipolar cycloaddition between azides and alkynes. Med. Res. Rev. 2008, 28, 278– 308, DOI: 10.1002/med.20107[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjsVerurg%253D&md5=ef565fc46c50047a6181e85711cb5c37Click chemistry reactions in medicinal chemistry: applications of the 1,3-dipolar cycloaddition between azides and alkynesTron, Gian Cesare; Pirali, Tracey; Billington, Richard A.; Canonico, Pier Luigi; Sorba, Giovanni; Genazzani, Armando A.Medicinal Research Reviews (2008), 28 (2), 278-308CODEN: MRREDD; ISSN:0198-6325. (John Wiley & Sons, Inc.)A review. In recent years, there has been an ever-increasing need for rapid reactions that meet the three main criteria of an ideal synthesis: efficiency, versatility, and selectivity. Such reactions would allow medicinal chem. to keep pace with the multitude of information derived from modern biol. screening techniques. The present review describes one of these reactions, the 1,3-dipolar cycloaddn. ("click-reaction") between azides and alkynes catalyzed by copper (I) salts. The simplicity of this reaction and the ease of purifn. of the resulting products have opened new opportunities in generating vast arrays of compds. with biol. potential. The present review will outline the accomplishments of this strategy achieved so far and outline some of medicinal chem. applications in which click-chem. might be relevant in the future.
- 35Hou, J.; Liu, X.; Shen, J.; Zhao, G.; Wang, P. G. The impact of click chemistry in medicinal chemistry. Expert Opin. Drug Discovery 2012, 7, 489– 501, DOI: 10.1517/17460441.2012.682725[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xns1SrtL0%253D&md5=6db4e8d966aec6a597971e3d9a2c605cThe impact of click chemistry in medicinal chemistryHou, Jingli; Liu, Xifang; Shen, Jie; Zhao, Guilong; Wang, Peng GeorgeExpert Opinion on Drug Discovery (2012), 7 (6), 489-501CODEN: EODDBX; ISSN:1746-0441. (Informa Healthcare)A review. Introduction: The copper(I)-catalyzed 1,3-dipolar cycloaddn. of alkynes and azides to form 1,2,3-triazoles is the most popular reaction in click chem. This reaction is also near-perfect, in terms of its robustness, due to the high degree of reliability and complete specificity. Furthermore, this reaction has been used increasingly in drug discovery, because the formed 1,2,3-triazole can act as both a bioisostere and a linker. Areas covered: This review provides an overview of a most important click reaction, 1,3-dipolar cycloaddns. of alkynes and azides, in the drug discovery.Expert opinion: Click chem. is a very powerful tool, in the drug discovery, because it is very efficient in the creation of compd. libraries through combinatorial methodol. However, the 1,2,3-triazole ring itself is not a commonly used pharmacophore and has rarely been found in marketed drugs, demonstrating that there are still some limitations during the use of 1,2,3-triazole in the mols. of drug candidates. Hopefully, in the next decade, we will witness the emergence of 1,2,3-triazole-bearing drugs on the market as this click reaction is used more and more widely in the drug discovery.
- 36Prasher, P.; Sharma, M. Tailored therapeutics based on 1,2,3-1H-triazoles: a mini review. MedChemComm 2019, 10, 1302– 1328, DOI: 10.1039/C9MD00218A[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpsVamt7g%253D&md5=4aab5704a66bbe69ee624a2b5280491bTailored therapeutics based on 1,2,3-1H-triazoles: a mini reviewPrasher, Parteek; Sharma, MousmeeMedChemComm (2019), 10 (8), 1302-1328CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Contemporary drug discovery approaches rely on library synthesis coupled with combinatorial methods and high-throughput screening to identify leads. However, due to the multitude of components involved, a majority of optimization techniques face persistent challenges related to the efficiency of synthetic processes and the purity of compd. libraries. These methods have recently found an upgradation as fragment-based approaches for target-guided synthesis of lead mols. with active involvement of their biol. target. The click chem. approach serves as a promising tool for tailoring the therapeutically relevant biomols. of interest, improving their bioavailability and bioactivity and redirecting them as efficacious drugs. 1,2,3-1H-Triazole nucleus, being a planar and biol. acceptable scaffold, plays a crucial role in the design of biomol. mimetics and tailor-made mols. with therapeutic relevance. This versatile scaffold also forms an integral part of the current fragment-based approaches for drug design, kinetic target guided synthesis and bioorthogonal methodologies.
- 37Chrysina, E. D.; Bokor, É.; Alexacou, K.-M.; Charavgi, M.-D.; Oikonomakos, G. N.; Zographos, S. E.; Leonidas, D. D.; Oikonomakos, N. G.; Somsák, L. Amide-1,2,3-triazole bioisosterism: the glycogen phosphorylase case. Tetrahedron: Asymmetry 2009, 20, 733– 740, DOI: 10.1016/j.tetasy.2009.03.021[Crossref], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtVeju74%253D&md5=99b5649d2eaeb32044b95945e816ae62Amide-1,2,3-triazole bioisosterism: the glycogen phosphorylase caseChrysina, Evangelia D.; Bokor, Eva; Alexacou, Kyra-Melinda; Charavgi, Maria-Despoina; Oikonomakos, George N.; Zographos, Spyros E.; Leonidas, Demetres D.; Oikonomakos, Nikos G.; Somsak, LaszloTetrahedron: Asymmetry (2009), 20 (6-8), 733-740CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)Per-O-acetylated β-D-glucopyranosyl azide was transformed into an intermediate iminophosphorane by PMe3 which was then acylated to N-acyl-β-D-glucopyranosylamines. The same azide and substituted acetylenes gave 1-(β-D-glucopyranosyl)-4-substituted-1,2,3-triazoles in Cu(I)-catalyzed azide-alkyne cycloaddns. Deprotection of these products by the Zemplen method furnished β-D-Glcp-NHCO-R derivs. I (R = ph, 1-naphthyl, 2-naphthyl, CH2OH) as well as 1-(β-D-Glcp)-4-R-1,2,3-triazoles II (R = ph, 1-naphthyl, 2-naphthyl, CH2OH) which were evaluated as inhibitors of rabbit muscle glycogen phosphorylase b. Pairs of amides vs. triazoles with the same R group displayed similar inhibition consts. X-ray crystallog. studies on the enzyme-inhibitor complexes revealed high similarities in the binding of pairs with R = 2-naphthyl and hydroxymethyl, while for the R = Ph and 1-naphthyl compds. a different orientation of the arom. part and changes in the conformation of the 280s loop were obsd. By this study new examples of amide-1,2,3-triazole bioisosteric relationship have been provided.
- 38Angell, Y. L.; Burgess, K. Peptidomimetics via copper-catalyzed azide-alkyne cycloadditions. Chem. Soc. Rev. 2007, 36, 1674– 1689, DOI: 10.1039/b701444a[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsVKit78%253D&md5=0b4a29de9c62148ffe459efef31c3f35Peptidomimetics via copper-catalyzed azide-alkyne cycloadditionsAngell, Yu L.; Burgess, KevinChemical Society Reviews (2007), 36 (10), 1674-1689CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. This crit. review concerns the impact of copper-mediated alkyne-azide cycloaddns. on peptidomimetic studies. It discusses how this reaction has been used to insert triazoles into peptide chains, to link peptides to other functionalities (e.g. carbohydrates, polymers, and labels), and as a basis for evolution of peptidomimetics as pharmaceutical leads. This work will be of interest to those studying "Click reaction", peptidomimetic secondary structure and function, and to medicinal chemists.
- 39Nathans, R.; Cao, H.; Sharova, N.; Ali, A.; Sharkey, M.; Stranska, R.; Stevenson, M.; Rana, T. M. Small-molecule inhibition of HIV-1 Vif. Nat. Biotechnol. 2008, 26, 1187– 1192, DOI: 10.1038/nbt.1496[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1aisr3K&md5=f80228275d0e19e40e049ea715c11895Small-molecule inhibition of HIV-1 VifNathans, Robin; Cao, Hong; Sharova, Natalia; Ali, Akbar; Sharkey, Mark; Stranska, Ruzena; Stevenson, Mario; Rana, Tariq M.Nature Biotechnology (2008), 26 (10), 1187-1192CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)The HIV-1 protein Vif, essential for in vivo viral replication, targets the human DNA-editing enzyme, APOBEC3G (A3G), which inhibits replication of retroviruses and hepatitis B virus. As Vif has no known cellular homologs, it is an attractive, yet unrealized, target for antiviral intervention. Although zinc chelation inhibits Vif and enhances viral sensitivity to A3G, this effect is unrelated to the interaction of Vif with A3G. We identify a small mol., RN-18, that antagonizes Vif function and inhibits HIV-1 replication only in the presence of A3G. RN-18 increases cellular A3G levels in a Vif-dependent manner and increases A3G incorporation into virions without inhibiting general proteasome-mediated protein degrdn. RN-18 enhances Vif degrdn. only in the presence of A3G, reduces viral infectivity by increasing A3G incorporation into virions and enhances cytidine deamination of the viral genome. These results demonstrate that the HIV-1 Vif-A3G axis is a valid target for developing small mol.-based new therapies for HIV infection or for enhancing innate immunity against viruses.
- 40Ali, A.; Wang, J.; Nathans, R. S.; Cao, H.; Sharova, N.; Stevenson, M.; Rana, T. M. Synthesis and structure-activity relationship studies of HIV-1 virion infectivity factor (Vif) inhibitors that block viral replication. ChemMedChem 2012, 7, 1217– 1229, DOI: 10.1002/cmdc.201200079[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsVansro%253D&md5=63cee4d4793348b9c67967d0680e9f2eSynthesis and Structure-Activity Relationship Studies of HIV-1 Virion Infectivity Factor (Vif) Inhibitors that Block Viral ReplicationAli, Akbar; Wang, Jinhua; Nathans, Robin S.; Cao, Hong; Sharova, Natalia; Stevenson, Mario; Rana, Tariq M.ChemMedChem (2012), 7 (7), 1217-1229, S1217/1-S1217/7CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)The human immunodeficiency virus 1 (HIV-1) virion infectivity factor (Vif) protein, essential for in vivo viral replication, protects the virus from innate antiviral cellular factor apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC3G; A3G) and is an attractive target for the development of novel antiviral therapeutics. We have evaluated the structure-activity relationships of N-(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide (RN-18), a small mol. recently identified as an inhibitor of Vif function that blocks viral replication only in nonpermissive cells expressing A3G, by inhibiting Vif-A3G interactions. Microwave-assisted cross-coupling reactions were developed to prep. a series of RN18 analogs with diverse linkages and substitutions on the Ph rings. A dual cell-based assay system was used to assess antiviral activity against wild-type HIV-1 in both nonpermissive (H9) and permissive (MT4) cells that also allowed evaluation of specificity. In general, variations of Ph substitutions were detrimental to antiviral potency and specificity, but isosteric replacements of amide and ether linkages were relatively well tolerated. These structure-activity relationship data define structural requirements for Vif-specific activity, identify new compds. with improved antiviral potency and specificity, and provide leads for further exploration to develop new antiviral therapeutics.
- 41Mohammed, I.; Parai, M. K.; Jiang, X.; Sharova, N.; Singh, G.; Stevenson, M.; Rana, T. M. SAR and lead optimization of an HIV-1 Vif-APOBEC3G axis inhibitor. ACS Med. Chem. Lett. 2012, 3, 465– 469, DOI: 10.1021/ml300037k[ACS Full Text], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmvV2gtbY%253D&md5=346201d67c71ec1e05d1a185e9c207efSAR and Lead Optimization of an HIV-1 Vif-APOBEC3G Axis InhibitorMohammed, Idrees; Parai, Maloy K.; Jiang, Xinpeng; Sharova, Natalia; Singh, Gatikrushna; Stevenson, Mario; Rana, Tariq M.ACS Medicinal Chemistry Letters (2012), 3 (6), 465-469CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We describe structure-activity relationship and optimization studies of RN-18 (I), an HIV-1 Vif-APOBEC3G axis inhibitor. Targeted modifications of RN-18 ring C, ring B, ring A, bridge A-B, and bridge B-C were performed to identify the crucial structural features, which generated new inhibitors with similar (4g and 4i) and improved (5, 8b, and 11) activities. Two potent water-sol. RN-18 analogs, 17 and 19, are also disclosed, and we describe the results of pharmacol. studies with compd. 19. The findings described here will be useful in the development of more potent Vif inhibitors and in the design of probes to identify the target protein of RN-18 and its analogs.
- 42Miller, J. H.; Presnyak, V.; Smith, H. C. The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G. Retrovirology 2007, 4, 81, DOI: 10.1186/1742-4690-4-81[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c%252FnvFansA%253D%253D&md5=7d29a637af09daa3373d5d3f25923e69The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3GMiller James H; Presnyak Vlad; Smith Harold CRetrovirology (2007), 4 (), 81 ISSN:.BACKGROUND: The HIV-1 accessory protein known as viral infectivity factor or Vif binds to the host defence factor human APOBEC3G (hA3G) and prevents its assembly with viral particles and mediates its elimination through ubiquitination and degradation by the proteosomal pathway. In the absence of Vif, hA3G becomes incorporated within viral particles. During the post entry phase of infection, hA3G attenuates viral replication by binding to the viral RNA genome and deaminating deoxycytidines to form deoxyuridines within single stranded DNA regions of the replicated viral genome. Vif dimerization has been reported to be essential for viral infectivity but the mechanistic requirement for Vif multimerization is unknown. RESULTS: We demonstrate that a peptide antagonist of Vif dimerization fused to the cell transduction domain of HIV TAT suppresses live HIV-1 infectivity. We show rapid cellular uptake of the peptide and cytoplasmic distribution. Robust suppression of viral infectivity was dependent on the expression of Vif and hA3G. Disruption of Vif multimerization resulted in the production of virions with markedly increased hA3G content and reduced infectivity. CONCLUSION: The role of Vif multimerization in viral infectivity of nonpermissive cells has been validated with an antagonist of Vif dimerization. An important part of the mechanism for this antiretroviral effect is that blocking Vif dimerization enables hA3G incorporation within virions. We propose that Vif multimers are required to interact with hA3G to exclude it from viral particles during their assembly. Blocking Vif dimerization is an effective means of sustaining hA3G antiretroviral activity in HIV-1 infected cells. Vif dimerization is therefore a validated target for therapeutic HIV-1/AIDS drug development.
- 43Ribeiro, A. C.; Maia e Silva, A.; Santa-Marta, M.; Pombo, A.; Moniz-Pereira, J.; Goncalves, J.; Barahona, I. Functional analysis of Vif protein shows less restriction of human immunodeficiency virus type 2 by APOBEC3G. J. Virol. 2005, 79, 823– 833, DOI: 10.1128/JVI.79.2.823-833.2005[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlt12itw%253D%253D&md5=ba45b7b49540573139a94c549897368bFunctional analysis of Vif protein shows less restriction of human immunodeficiency virus type 2 by APOBEC3GRibeiro, Ana Clara; Maia e Silva, Alexandra; Santa-Marta, Mariana; Pombo, Ana; Moniz-Pereira, Jose; Goncalves, Joao; Barahona, IsabelJournal of Virology (2005), 79 (2), 823-833CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)Viral infectivity factor (Vif) is one of the human immunodeficiency virus (HIV) accessory proteins and is conserved in the primate lentivirus group. This protein is essential for viral replication in vivo and for productive infection of nonpermissive cells, such as peripheral blood mononuclear cells (PBMC). Vif counteracts an antiretroviral cellular factor in nonpermissive cells named CEM15/APOBEC3G. Although HIV type 1 (HIV-1) Vif protein (Vif1) can be functionally replaced by HIV-2 Vif protein (Vif2), its identity is very small. Most of the functional studies have been carried out with Vif1. Characterization of functional domains of Vif2 may elucidate its function, as well as differences between HIV-1 and HIV-2 infectivity. Our aim was to identify the permissivity of different cell lines for HIV-2 vif-minus viruses. By mutagenesis specific conserved motifs of HIV-2 Vif protein were analyzed, as well as in conserved motifs between Vif1 and Vif2 proteins. Vif2 mutants were examd. for their stability, expression, and cellular localization in order to characterize essential domains of Vif2 proteins. Viral replication in various target cells (PBMC and H9, A3.01, U38, and Jurkat cells) and infectivity in single cycle assays in the presence of APOBEC3G were also analyzed. Our results of viral replication show that only PBMC have a nonpermissive phenotype in the absence of Vif2. Moreover, the HIV-1 vif-minus nonpermissive cell line H9 does not show a similar phenotype for vif-neg. HIV-2. We also report a limited effect of APOBEC3G in a single-cycle infectivity assay, where only conserved domains between HIV-1 and HIV-2 Vif proteins influence viral infectivity. Taken together, these results allow us to speculate that viral inhibition by APOBEC3G is not the sole and most important determinant of antiviral activity against HIV-2.
- 44Mohammed, I.; Kummetha, I. R.; Singh, G.; Sharova, N.; Lichinchi, G.; Dang, J.; Stevenson, M.; Rana, T. M. 1,2,3-Triazoles as amide bioisosteres: discovery of a new class of potent HIV-1 Vif antagonists. J. Med. Chem. 2016, 59, 7677– 7682, DOI: 10.1021/acs.jmedchem.6b00247[ACS Full Text], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlSltb7F&md5=f75735900056b2f0975a13a8b6d7355a1,2,3-Triazoles as Amide Bioisosteres: Discovery of a New Class of Potent HIV-1 Vif AntagonistsMohammed, Idrees; Kummetha, Indrasena Reddy; Singh, Gatikrushna; Sharova, Natalia; Lichinchi, Gianluigi; Dang, Jason; Stevenson, Mario; Rana, Tariq M.Journal of Medicinal Chemistry (2016), 59 (16), 7677-7682CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)RN-18 based viral infectivity factor (Vif), Vif antagonists reduce viral infectivity by rescuing APOBEC3G (A3G) expression and enhancing A3G-dependent Vif degrdn. Replacement of amide functionality in RN-18 (IC50 = 6 μM) by isosteric heterocycles resulted in the discovery of a 1,2,3-trizole, 1d (IC50 = 1.2 μM). We identified several potent HIV-1 inhibitors from a 1d based library including 5ax (IC50 = 0.01 μM), 5bx (0.2 μM), 2ey (0.4 μM), 5ey (0.6 μM), and 6bx (0.2 μM).
- 45Rudin, C. M. Vismodegib. Clin. Cancer Res. 2012, 18, 3218– 3222, DOI: 10.1158/1078-0432.CCR-12-0568[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xos1Olt7Y%253D&md5=734079d44b61c0d8a28881dc9adda83aVismodegibRudin, Charles M.Clinical Cancer Research (2012), 18 (12), 3218-3222CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)A review. Vismodegib (GDC-0449), an orally bioavailable small-mol. inhibitor of Hedgehog signaling, was recently approved by the U.S. Food and Drug Administration for the treatment of basal cell carcinoma that is either metastatic or locally advanced in patients who are not candidates for surgical resection or radiation. Given the absence of previously defined effective drug therapy for this disease, approval was granted primarily on the basis of outcome of a nonrandomized parallel cohort phase II study of 99 patients with advanced basal cell carcinoma, with a primary endpoint of objective response rate. Response rates of 30.3% and 42.9% were obsd. in metastatic and locally advanced cohorts in this study, resp., assocd. with median progression-free survival in both cohorts of 9.5 mo. Ongoing clin. investigations include evaluation of the potential efficacy of vismodegib in a variety of diseases and in combination with other agents. The mechanism of action, preclin. and clin. data, and potential utility in other disease contexts are reviewed here. Clin Cancer Res; 18(12); 3218-22. ©2012 AACR.
- 46Cirrone, F.; Harris, C. S. Vismodegib and the hedgehog pathway: a new treatment for basal cell carcinoma. Clin. Ther. 2012, 34, 2039– 2050, DOI: 10.1016/j.clinthera.2012.08.011[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFSlsrjN&md5=62f4be4d8c749dd74f2a8e7d304447e4Vismodegib and the Hedgehog Pathway: A New Treatment for Basal Cell CarcinomaCirrone, Frank; Harris, Christy S.Clinical Therapeutics (2012), 34 (10), 2039-2050CODEN: CLTHDG; ISSN:0149-2918. (Elsevier)A review. Background: Vismodegib is an oral inhibitor of the Hedgehog pathway approved by the US Food and Drug Administration. It is the first systemic treatment for patients with locally advanced or metastatic basal cell carcinoma that is not amenable to surgery and radiation. This is the first drug to use the Hedgehog pathway to inhibit the proliferation of tumors and is also implicated in the development of other cancers such as medulloblastoma. Objective: The goal of this review was to summarize the development, pharmacol., efficacy, and safety of vismodegib. Methods: Relevant English-language literature was identified and then evaluated based on results from database searches of MEDLINE and EMBASE from 1975 to June 19, 2012. The terms searched included, but were not limited to, vismodegib, Erivedge, GDC-0449, basal cell carcinoma, and 2-chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]-4-(methylsulfonyl)benzamide. Addnl. literature was identified by assessing the ref. lists of previously identified articles and through abstrs. presented by the American Society of Clin. Oncol. Results: A total of 70 full text citations were identified although two national conference proceedings were then excluded. An addnl. 10 published abstrs. were also identified. A Phase II, nonrandomized, multicenter, international study demonstrated a 30.3% objective response rate in metastatic basal cell carcinoma and a 42.9% objective response rate in locally advanced basal cell carcinoma. The adverse effect profile for vismodegib is similar to other identified Hedgehog pathway inhibitors; muscle cramps (71.7%), alopecia (63.8%), and dysgeusia (55.1%) were the most common adverse effects seen in trials. A Phase II, randomized, placebo-controlled trial in Gorlin syndrome patients with basal cell carcinoma concluded that vismodegib was significantly better than placebo at reducing new basal cell carcinoma lesions (P < 0.001) and at decreasing the sum of the longest diam. of existing lesions (P = 0.003). Conclusions: For patients with unresectable basal cell carcinoma or where resection would be cosmetically disadvantageous, vismodegib is an effective therapy with good response rates. At this time, the data are too limited to det. overall survival. The Hedgehog pathway is a newly identified area in which mutations or dysregulation can occur, leading to the development and progression of tumors. Studies continue to look at other cancers with involvement of the Hedgehog pathway.
- 47Koelblinger, P.; Lang, R. New developments in the treatment of basal cell carcinoma: update on current and emerging treatment options with a focus on vismodegib. OncoTargets Ther. 2018, 11, 8327– 8340, DOI: 10.2147/OTT.S135650[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlKntrvK&md5=ba0dbaca1e5c8c8526b4cad32353450fNew developments in the treatment of basal cell carcinoma: update on current and emerging treatment options with a focus on vismodegibKoelblinger, Peter; Lang, RolandOncoTargets and Therapy (2018), 11 (), 8327-8340CODEN: OTNHAZ; ISSN:1178-6930. (Dove Medical Press Ltd.)Basal cell carcinoma (BCC) is the most common form of skin cancer worldwide. Although most BCCs can be treated by relatively simple surgical or nonsurgical methods, some patients with BCC may eventually develop advanced disease which can either be locally destructive or even include metastatic spread. The present review summarizes the current literature on the treatment of both early and advanced BCC with a focus on the hedgehog inhibitor vismodegib which has become an integral part of the management of patients with advanced BCC since its regulatory approval in 2012.
- 48Sharpe, H. J.; Pau, G.; Dijkgraaf, G. J.; Basset-Seguin, N.; Modrusan, Z.; Januario, T.; Tsui, V.; Durham, A. B.; Dlugosz, A. A.; Haverty, P. M.; Bourgon, R.; Tang, J. Y.; Sarin, K. Y.; Dirix, L.; Fisher, D. C.; Rudin, C. M.; Sofen, H.; Migden, M. R.; Yauch, R. L.; de Sauvage, F. J. Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell 2015, 27, 327– 341, DOI: 10.1016/j.ccell.2015.02.001[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXktFOgtrs%253D&md5=fe0aa6db03295a3250a3e7c3679e08f4Genomic Analysis of Smoothened Inhibitor Resistance in Basal Cell CarcinomaSharpe, Hayley J.; Pau, Gregoire; Dijkgraaf, Gerrit J.; Basset-Seguin, Nicole; Modrusan, Zora; Januario, Thomas; Tsui, Vickie; Durham, Alison B.; Dlugosz, Andrzej A.; Haverty, Peter M.; Bourgon, Richard; Tang, Jean Y.; Sarin, Kavita Y.; Dirix, Luc; Fisher, David C.; Rudin, Charles M.; Sofen, Howard; Migden, Michael R.; Yauch, Robert L.; de Sauvage, Frederic J.Cancer Cell (2015), 27 (3), 327-341CODEN: CCAECI; ISSN:1535-6108. (Elsevier Inc.)Smoothened (SMO) inhibitors are under clin. investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clin. benefit on vismodegib, but some develop resistance. Genomic anal. of tumor biopsies revealed that vismodegib resistance is assocd. with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy no. changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.
- 49Christodoulou, M. S.; Mori, M.; Pantano, R.; Alfonsi, R.; Infante, P.; Botta, M.; Damia, G.; Ricci, F.; Sotiropoulou, P. A.; Liekens, S.; Botta, B.; Passarella, D. Click reaction as a tool to combine pharmacophores: the case of vismodegib. ChemPlusChem 2015, 80, 938– 943, DOI: 10.1002/cplu.201402435[Crossref], [PubMed], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptFeqtLo%253D&md5=89723c9311c7de4d295eafcef5a3898dClick Reaction as a Tool to Combine Pharmacophores: The Case of VismodegibChristodoulou, Michael S.; Mori, Mattia; Pantano, Rebecca; Alfonsi, Romina; Infante, Paola; Botta, Maurizio; Damia, Giovanna; Ricci, Francesca; Sotiropoulou, Panagiota A.; Liekens, Sandra; Botta, Bruno; Passarella, DanieleChemPlusChem (2015), 80 (6), 938-943CODEN: CHEMM5; ISSN:2192-6506. (Wiley-VCH Verlag GmbH & Co. KGaA)The design and the prepn. of a small library of 1,4-diphenyl-1,2,3-triazole derivs. is reported, with the aim to obtain a new class of Hedgehog pathway inhibitors. The smoothened protein is part of the hedgehog signaling pathway that is inhibited by the lead compd. Vismodegib. Based on mol. modeling simulations, seven triazole derivs. of Vismodegib are synthesized and their biol. effect on different endothelial, cancer, and cancer stem cell lines is reported.
- 50Colombo, F.; Tintori, C.; Furlan, A.; Borrelli, S.; Christodoulou, M. S.; Dono, R.; Maina, F.; Botta, M.; Amat, M.; Bosch, J.; Passarella, D. ‘Click’ synthesis of a triazole-based inhibitor of Met functions in cancer cells. Bioorg. Med. Chem. Lett. 2012, 22, 4693– 4696, DOI: 10.1016/j.bmcl.2012.05.078[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xpt1Sgsbo%253D&md5=1fb77daf5aaff3028bca30587b940d63'Click' synthesis of a triazole-based inhibitor of Met functions in cancer cellsColombo, Francesco; Tintori, Cristina; Furlan, Alessandro; Borrelli, Stella; Christodoulou, Michael S.; Dono, Rosanna; Maina, Flavio; Botta, Maurizio; Amat, Mercedes; Bosch, Joan; Passarella, DanieleBioorganic & Medicinal Chemistry Letters (2012), 22 (14), 4693-4696CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The use of Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddn. permitted the synthesis of a new compd. (I) that is able to inhibit the HGF-induced scattering of MDCK (epithelial cells) and in vitro tumorigenesis of H1437 (non-small-cell lung cancer) and GTL-16 (human gastric carcinoma). In agreement with biochem. and biol. results, docking studies within the ATP binding site of Met suggested for the new synthesized compd. a binding mode similar to that of the active compd. Triflorcas previously reported.
- 51Furlan, A.; Roux, B.; Lamballe, F.; Conti, F.; Issaly, N.; Daian, F.; Guillemot, J. F.; Richelme, S.; Contensin, M.; Bosch, J.; Passarella, D.; Piccolo, O.; Dono, R.; Maina, F. Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures. PLoS One 2012, 7, e46738 DOI: 10.1371/journal.pone.0046738[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFCis7%252FI&md5=65339ecf250f39c9234abae6c8f95429Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signaturesFurlan, Alessandro; Roux, Benjamin; Lamballe, Fabienne; Conti, Filippo; Issaly, Nathalie; Daian, Fabrice; Guillemot, Jean-Francois; Richelme, Sylvie; Contensin, Magali; Bosch, Joan; Passarella, Daniele; Piccolo, Oreste; Dono, Rosanna; Maina, FlavioPLoS One (2012), 7 (10), e46738CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)The development of targeted mol. therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for mol. therapies. 2-Phenylimidazo[2,1-b]benzothiazole derivs. have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by "RTK swapping" by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addn. to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addn. to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivs. through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation.
- 52Arioli, F.; Borrelli, S.; Colombo, F.; Falchi, F.; Filippi, I.; Crespan, E.; Naldini, A.; Scalia, G.; Silvani, A.; Maga, G.; Carraro, F.; Botta, M.; Passarella, D. N-[2-methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine as a scaffold for the synthesis of inhibitors of Bcr-Abl. ChemMedChem 2011, 6e, 2009– 2018, DOI: 10.1002/cmdc.201100304
- 53Buchdunger, E.; O’Reilley, T.; Wood, J. Pharmacology of imatinib (STI571). Eur. J. Cancer 2002, 38 (Suppl. 5), S28– S36, DOI: 10.1016/S0959-8049(02)80600-1
- 54Hernandez-Boluda, J. C.; Cervantes, F. Imatinib mesylate (gleevec, glivec): a new therapy for chronic myeloid leukemia and other malignancies. Drugs Today (Barc) 2002, 38, 601– 613, DOI: 10.1358/dot.2002.38.9.696536[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s%252FntFequg%253D%253D&md5=3917aa8f7e8d02d13aaaffc683153272Imatinib mesylate (Gleevec, Glivec): a new therapy for chronic myeloid leukemia and other malignanciesHernandez-Boluda Juan Carlos; Cervantes FranciscoDrugs of today (Barcelona, Spain : 1998) (2002), 38 (9), 601-13 ISSN:1699-3993.Imatinib mesylate (STI571, Gleevec, Glivec, a selective inhibitor of the BCR-ABL tyrosine kinase causative of chronic myeloid leukemia (CML), represents the paradigm of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a targeted molecular therapy. Phase II clinical trials have shown marked therapeutic activity of imatinib in all evolutive phases of CML, but notably in the chronic phase, where it induces complete hematological responses in almost 100% of patients resistant or intolerant to interferon, with a major cytogenetic response rate of 60%, including 41% complete cytogenetic responses. The preliminary results of an ongoing phase III multicenter randomized study comparing imatinib with interferon plus cytarabine as first-line treatment for CML favor imatinib in terms of efficacy and safety. If confirmed with longer follow-up,these results would establish imatinib as the choice therapy for the majority of CML patients, with allogeneic transplantation being restricted as initial therapy only to younger patients with a family donor. Longer follow-up will answer some questions, such as those on long-term safety, durability of the responses, whether these will translate into a survival prolongation and the possibility of molecular responses. In addition, further information on the mechanisms involved in the primary and acquired resistance to imatinib is needed. Besides the Bcr-Abl protein, the drug is also active against other tyrosine kinases, such as Abl, the stem-cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this sense, it must be pointed out that imatinib has shown a remarkable activity in gastrointestinal stromal tumors.
- 55Moen, M. D.; McKeage, K.; Plosker, G. L.; Siddiqui, M. A. Imatinib: a review of its use in chronic myeloid leukaemia. Drugs 2007, 67, 299– 320, DOI: 10.2165/00003495-200767020-00010[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXksFOjsbk%253D&md5=b347c3ad7678bc9e17aaadbebd6cda53Imatinib: a review of its use in chronic myeloid leukaemiaMoen, Marit D.; McKeage, Kate; Plosker, Greg L.; Siddiqui, M. Asif A.; Berman, E.; Gambacorti-Passerini, C.; Goldman, J. H.; Hochhaus, A.; Larson, R. A.; Rosti, G.; Simonsson, B.Drugs (2007), 67 (2), 299-320CODEN: DRUGAY; ISSN:0012-6667. (Adis International Ltd.)A review. Imatinib (Gleevec, Glivec) is a synthetic tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (CML). It is specifically designed to inhibit the breakpoint cluster region (BCR)-Abelson (ABL) fusion protein that results from the chromosomal abnormality known as the Philadelphia chromosome. CML is characterized by this abnormality, which leads to abnormalities of the peripheral blood and bone marrow including an increase in the no. of granular leukocytes. Imatinib is approved in numerous countries worldwide for the treatment of newly diagnosed Philadelphia chromosome-pos. (Ph+) chronic-phase CML, Ph+ accelerated-phase or blast-crisis CML, and in patients with Ph+ chronic-phase CML who have failed to respond to interferon-α therapy. It is also indicated in pediatric patients with newly diagnosed Ph+ chronic-phase CML, in accelerated-phase or blast-crisis CML, or in chronic-phase CML after failure of interferon-α therapy or when the disease has recurred after hematopoietic stem cell transplantation (HSCT). Approved indications, however, may vary by country. Imatinib is effective and generally well tolerated in patients with Ph+ CML. In patients with newly diagnosed chronic-phase CML, imatinib was more effective than interferon-α plus cytarabine in preventing progression of the disease and in achieving haematol. and cytogenetic responses. Overall survival rates remain high after 5 years of follow-up, and historical comparisons with other treatments demonstrate improved overall survival with imatinib in the long term. Patients with accelerated-phase or blast-crisis CML, or those who have not responded to prior interferon-α therapy also benefit from imatinib treatment. Some patients become resistant or intolerant to imatinib therapy; management strategies to overcome these problems include dosage adjustment, other treatments, or combination therapy with imatinib and other agents. Allogeneic HSCT is currently the only potentially curative treatment, but it is assocd. with high rates of morbidity and mortality and is not suitable for all patients. The introduction of imatinib has had a marked impact on outcomes in patients with CML. It remains a valuable treatment for all stages of the disease, esp. initial treatment of newly diagnosed Ph+ chronic-phase CML, and is endorsed by European and US treatment guidelines as a first-line option. Pharmacol. Properties Imatinib inhibits BCR-ABL tyrosine kinase, which is expressed by CML cells with the Philadelphia chromosome abnormality. It also inhibits the receptor tyrosine kinases for platelet-derived growth factor and stem cell factor. Administration of imatinib to CML patients results in marked changes in bone marrow histopathol. and normalization of bone marrow vascularity in some patients. Primary or acquired resistance to imatinib is common in patients with advanced CML. There are several mechanisms of resistance and most involve reactivation of BCR-ABL signalling. Serial measurements of BCR-ABL transcript levels and ABL mutational screening can help identify the presence of BCR-ABL tyrosine kinase domain mutations and thereby emerging resistance. Following oral administration, imatinib is rapidly absorbed. The bioavailability of imatinib is 98%, and peak plasma concns. are reached after 2-4 h. Imatinib is metabolized by the liver and is primarily eliminated via the feces as unchanged parent drug and metabolites. Dosage adjustments are recommended in patients with severe hepatic dysfunction. Systemic exposure of imatinib may be altered when the drug is coadministered with various cytochrome P 450 inducers or inhibitors. Therapeutic Efficacy In a randomized, nonblind, multicenter phase III trial in patients with newly diagnosed Ph+ chronic-phase CML, imatinib significantly improved the estd. rates of survival without progression and survival without progression to accelerated-phase or blast-crisis CML compared with interferon-α plus cytarabine at median follow-ups of 19 and 30 mo. Haematol. and cytogenetic responses were also significantly greater in the imatinib group at both follow-ups. Rates of freedom from progression and haematol. and cytogenetic response remained high in imatinib recipients at a 60-mo follow-up of the phase III trial, although comparisons with interferon-α plus cytarabine recipients were not possible, as the majority of those randomized to interferon-α plus cytarabine had crossed over to the imatinib treatment arm. For the same reason, a between-treatment group comparison of overall survival in the phase III study was not possible. In an historical comparison between different trials, overall survival rates at 36 mo for imatinib recipients in the phase III trial were significantly higher than those for interferon-α plus cytarabine recipients in another study. Imatinib also produced high rates of haematol. and cytogenetic responses in phase II trials of Ph+ patients with accelerated-phase or blast-crisis CML, and in those who received second-line imatinib, with long-term follow-up (median 60 mo), after failure of interferon-α therapy. Cost-effectiveness analyses generally predict that imatinib is a costly, but generally cost-effective, treatment option; it is more effective and less costly than bone marrow transplantation. Tolerability Imatinib was generally well tolerated. Most imatinib recipients in the phase II and III studies experienced adverse events, usually of mild to moderate severity. The most common nonhaematol. adverse events in patients with chronic-phase CML were superficial edema, muscle cramps, diarrhea, nausea and musculo-skeletal pain. Similar tolerability profiles were seen in the phase II studies in patients with accelerated-phase or blast-crisis CML, and in those who had failed to respond to prior therapy with interferon-α. Grade 3 or 4 neutropenia, thrombocytopenia and anemia occurred in imatinib recipients in all phase II studies and in the phase III study, and appeared to be more severe in patients with advanced disease. In patients with chronic-phase CML in the phase III study, the incidences of grade 3 plus 4 neutropenia and thrombocytopenia were significantly lower in imatinib recipients than in those who received interferon-α plus cytarabine.
- 56Waller, C. F. Imatinib mesylate. Recent Results Cancer Res. 2010, 184, 3– 20, DOI: 10.1007/978-3-642-01222-8_1[Crossref], [PubMed], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlKgsLnM&md5=8a17d6a0511083508841a45d35a8de46Imatinib mesylateWaller, Cornelius F.Recent Results in Cancer Research (2010), 184 (Small Molecules in Oncology), 3-20CODEN: RRCRBU; ISSN:0080-0015. (Springer GmbH)A review. IMATINIB MESYLATE (Gleevec, Glivec [Novartis, Basel, Switzerland], formerly referred to as STI571 or CGP57148B) represents the paradigm of a new class of anticancer agents, the so-called small mols. They have a high selectivity against a specific mol. target known to be the cause for the establishment and maintenance of the malignant phenotype. Imatinib is a rationally designed oral signal transduction inhibitor that specifically targets several protein tyrosine kinases, Abl, Arg (Abl-related gene), the stem-cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGF-R), and their oncogenic forms, most notably Bcr-Abl. Imatinib has been shown to have remarkable clin. activity in patients with chronic myeloid leukemia (CML) and malignant gastrointestinal stroma tumors (GIST) leading to its approval for treatment of these diseases. Treatment with imatinib is generally well tolerated with a low incidence of severe side effects. The most common adverse events (AE) include mild to moderate edema, muscle cramps, diarrhea, nausea, skin rashes, and myelosuppression. Several mechanisms of resistance have been identified. Clonal evolution, amplification, or overexpression of Bcr-Abl as well as mutations in the catalytic domain, P-loop, and other mutations have been demonstrated to play a role in primary and secondary resistance to imatinib, resp. Improved understanding of the underlying mechanisms of resistance has led to the development of new second-generation tyrosine kinase inhibitors.
- 57Iqbal, N.; Iqbal, N. Imatinib: a breakthrough of targeted therapy in cancer. Chemother. Res. Pract. 2014, 2014, 357027, DOI: 10.1155/2014/357027[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfmsF2ntQ%253D%253D&md5=a11c9083960b6e9fb322a5671fbbc9d1Imatinib: a breakthrough of targeted therapy in cancerIqbal Nida; Iqbal NaveedChemotherapy research and practice (2014), 2014 (), 357027 ISSN:2090-2107.Deregulated protein tyrosine kinase activity is central to the pathogenesis of human cancers. Targeted therapy in the form of selective tyrosine kinase inhibitors (TKIs) has transformed the approach to management of various cancers and represents a therapeutic breakthrough. Imatinib was one of the first cancer therapies to show the potential for such targeted action. Imatinib, an oral targeted therapy, inhibits tyrosine kinases specifically BCR-ABL, c-KIT, and PDGFRA. Apart from its remarkable success in CML and GIST, Imatinib benefits various other tumors caused by Imatinib-specific abnormalities of PDGFR and c-KIT. Imatinib has also been proven to be effective in steroid-refractory chronic graft-versus-host disease because of its anti-PDGFR action. This paper is a comprehensive review of the role of Imatinib in oncology.
- 58Schenone, S.; Bruno, O.; Radi, M.; Botta, M. New insights into small-molecule inhibitors of Bcr-Abl. Med. Res. Rev. 2011, 31, 1– 41, DOI: 10.1002/med.20175[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M%252Fis12gsA%253D%253D&md5=31f5f6ac39058db5fc2b49e80f0124deNew insights into small-molecule inhibitors of Bcr-AblSchenone S; Bruno O; Radi M; Botta MMedicinal research reviews (2011), 31 (1), 1-41 ISSN:.Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a defined genetic abnormality, the Bcr-Abl fusion gene on the Philadelphia chromosome that expresses the constitutively activated tyrosine kinase (TK) Bcr-Abl. This enzyme leads to the malignant transformation of primitive hematopoietic cells and to the consequent disease. The central role of Bcr-Abl in the pathogenesis of CML culminated in the discovery of imatinib (an ATP-competitive inhibitor), which is currently the frontline therapy for CML. Unfortunately, the initial enthusiasm generated by its high response rate has been dampened by the development of resistance, especially in the advanced phases of CML. To overcome imatinib resistance, several second-generation ATP-competitive inhibitors endowed with increased potency against imatinib-resistant mutants have been developed: the dual Src/Abl inhibitor dasatinib and the Abl inhibitor nilotinib have been recently approved by US-FDA for the treatment of imatinib-resistant CML, and many other compounds are currently in clinical trial. Although second-generation TK inhibitors have shown to be clinically effective against most of the imatinib-resistant mutants, to date poor results have been obtained in the treatment of the Bcr-Abl T315I mutant. In this review we will report the most interesting second-generation Abl and dual Src/Abl inhibitors recently entered in clinical trial, but also the new ATP-competitive and uncompetitive inhibitors published in the last few years, focusing on their chemical structure, mechanism of action, and structure-activity relationship.
- 59Leggio, G. M.; Bucolo, C.; Platania, C. B.; Salomone, S.; Drago, F. Current drug treatments targeting dopamine D3 receptor. Pharmacol. Ther. 2016, 165, 164– 177, DOI: 10.1016/j.pharmthera.2016.06.007[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVGisbfF&md5=e29dffe5b17b48f68d33ec838ece35dcCurrent drug treatments targeting dopamine D3 receptorLeggio, Gian Marco; Bucolo, Claudio; Platania, Chiara Bianca Maria; Salomone, Salvatore; Drago, FilippoPharmacology & Therapeutics (2016), 165 (), 164-177CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)Dopamine receptors (DR) have been extensively studied, but only in recent years they became object of investigation to elucidate the specific role of different subtypes (D1R, D2R, D3R, D4R, D5R) in neural transmission and circuitry. D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D2R and D4R) differ in signal transduction, binding profile, localization in the central nervous system and physiol. effects. D3R is involved in a no. of pathol. conditions, including schizophrenia, Parkinson's disease, addiction, anxiety, depression and glaucoma. Development of selective D3R ligands has been so far challenging, due to the high sequence identity and homol. shared by D2R and D3R. As a consequence, despite a rational design of selective DR ligands has been carried out, none of currently available medicines selectively target a given D2-like receptor subtype. The availability of the D3R ligand [11C]-(+)-PHNO for positron emission tomog. studies in animal models as well as in humans, allows researchers to est. the expression of D3R in vivo; displacement of [11C]-(+)-PHNO binding by concurrent drug treatments is used to est. the in vivo occupancy of D3R. Here we provide an overview of studies indicating D3R as a target for pharmacol. therapy, and a review of market approved drugs endowed with significant affinity at D3R that are used to treat disorders where D3R plays a relevant role.
- 60Joyce, J. N. Dopamine D3 receptor as a therapeutic target for antipsychotic and antiparkinsonian drugs. Pharmacol. Ther. 2001, 90, 231– 259, DOI: 10.1016/S0163-7258(01)00139-5[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXntV2hur8%253D&md5=70af1ac4de6b531b5b3b13f0fe179d0fDopamine D3 receptor as a therapeutic target for antipsychotic and antiparkinsonian drugsJoyce, J. N.Pharmacology & Therapeutics (2001), 90 (2-3), 231-259CODEN: PHTHDT; ISSN:0163-7258. (Elsevier Science Inc.)A review. The cloning of the gene for the D3 receptor and subsequent identification of its distribution in brain and pharmacol. allowed for serious consideration of the possibility that it might be a target for drugs used to treat schizophrenia and Parkinson's disease (PD). That is because it is highly expressed in limbic regions of the brain, exhibits low expression in motor divisions, and has pharmacol. similarity to the D2 receptor. Thus, antipsychotics that were presumed to block D2 receptors also had high affinity for the D3 receptor. Dopamine agonists used to treat the clin. symptoms of PD also have high affinity for the D3 receptor, and two D3 receptor-preferring agonists were effective for treatment of PD. Many compds. achieving high potency and selectivity are now available, but few have reached clin. testing. Recent findings with respect to the anatomy of this receptor in human brain, altered expression in schizophrenia and PD, and biol. models to study its function support the proposal that it is a target for development of drugs to alleviate symptoms in neuropsychiatric and neurol. disorders. Because of distinct aspects of regulation of the D3 receptor, it represents a unique target for therapeutic intervention in schizophrenia without high potential for unintended side effects such as tardive dyskinesia. It may also be that D3 receptor agonists can provide neuroprotective effects in PD and can modify clin. symptoms that D2 receptor-preferring agonists cannot provide.
- 61Maramai, S.; Gemma, S.; Brogi, S.; Campiani, G.; Butini, S.; Stark, H.; Brindisi, M. Dopamine D3 receptor antagonists as potential therapeutics for the treatment of neurological diseases. Front. Neurosci. 2016, 10, 451, DOI: 10.3389/fnins.2016.00451[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srktFCktA%253D%253D&md5=03b1e02b49ea48ab9331f5c9d38dfaf1Dopamine D3 Receptor Antagonists as Potential Therapeutics for the Treatment of Neurological DiseasesMaramai Samuele; Gemma Sandra; Brogi Simone; Campiani Giuseppe; Butini Stefania; Brindisi Margherita; Stark HolgerFrontiers in neuroscience (2016), 10 (), 451 ISSN:1662-4548.D3 receptors represent a major focus of current drug design and development of therapeutics for dopamine-related pathological states. Their close homology with the D2 receptor subtype makes the development of D3 selective antagonists a challenging task. In this review, we explore the relevance and therapeutic utility of D3 antagonists or partial agonists endowed with multireceptor affinity profile in the field of central nervous system disorders such as schizophrenia and drug abuse. In fact, the peculiar distribution and low brain abundance of D3 receptors make them a valuable target for the development of drugs devoid of motor side effects classically elicited by D2 antagonists. Recent research efforts were devoted to the conception of chemical templates possibly endowed with a multi-target profile, especially with regards to other G-protein-coupled receptors (GPCRs). A comprehensive overview of the recent literature in the field is herein provided. In particular, the evolution of the chemical templates has been tracked, according to the growing advancements in both the structural information and the refinement of the key pharmacophoric elements. The receptor/multireceptor affinity and functional profiles for the examined compounds have been covered, together with their most significant pharmacological applications.
- 62Newman, A. H.; Grundt, P.; Cyriac, G.; Deschamps, J. R.; Taylor, M.; Kumar, R.; Ho, D.; Luedtke, R. R. N-(4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with functionalized linking chains as high affinity and enantioselective D3 receptor antagonists. J. Med. Chem. 2009, 52, 2559– 2570, DOI: 10.1021/jm900095y[ACS Full Text], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktFGrt7s%253D&md5=665731381e379cec45ef058cd6c45d0eN-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor AntagonistsNewman, Amy Hauck; Grundt, Peter; Cyriac, George; Deschamps, Jeffrey R.; Taylor, Michelle; Kumar, Rakesh; Ho, David; Luedtke, Robert R.Journal of Medicinal Chemistry (2009), 52 (8), 2559-2570CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl- and 2-OCH3-phenylpiperazine class of compds. with the goal to improve D3 receptor affinity and selectivity. This extension of structure-activity relationships (SAR) has resulted in the identification of the first enantioselective D3 antagonists (R- and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2, and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compds. reported to date that show high affinity (Ki = 1 nM) for D3 and ∼400-fold selectivity over the D2 receptor subtype. Several of these analogs showed exquisite selectivity for D3 receptors over >60 other receptors, further underscoring their value as in vivo research tools. These lead compds. also have appropriate phys. characteristics for in vivo exploration and therefore will be useful in detg. how intrinsic activity at D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric disorders.
- 63Boateng, C. A.; Bakare, O. M.; Zhan, J.; Banala, A. K.; Burzynski, C.; Pommier, E.; Keck, T. M.; Donthamsetti, P.; Javitch, J. A.; Rais, R.; Slusher, B. S.; Xi, Z. X.; Newman, A. H. High affinity dopamine D3 Receptor (D3R)-selective antagonists attenuate heroin self-administration in wild-type but not D3R knockout mice. J. Med. Chem. 2015, 58, 6195– 6213, DOI: 10.1021/acs.jmedchem.5b00776[ACS Full Text], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1alur%252FK&md5=1724065cac8ac51295cf4660a20ed734High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout MiceBoateng, Comfort A.; Bakare, Oluyomi M.; Zhan, Jia; Banala, Ashwini K.; Burzynski, Caitlin; Pommier, Elie; Keck, Thomas M.; Donthamsetti, Prashant; Javitch, Jonathan A.; Rais, Rana; Slusher, Barbara S.; Xi, Zheng-Xiong; Newman, Amy HauckJournal of Medicinal Chemistry (2015), 58 (15), 6195-6213CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The dopamine D3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models of drug abuse, esp. in models of relapse. Nevertheless, poor bioavailability, metabolic instability, and/or predicted toxicity have impeded success in translating these drug candidates to clin. use. Herein, the authors report a series of D3R-selective 4-phenylpiperazines with improved metabolic stability. A subset of these compds. was evaluated for D3R functional efficacy and off-target binding at selected 5-HT receptor subtypes, where significant overlap in SAR with D3R has been obsd. Several high affinity D3R antagonists, including compds. I (Ki = 0.12 nM) and II (Ki = 0.35 nM), showed improved metabolic stability compared to the parent compd., PG648. Notably, I and the classic D3R antagonist SB277011A were effective in reducing self-administration of heroin in wild-type but not D3R knockout mice.
- 64Heidbreder, C. A.; Newman, A. H. Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders. Ann. N. Y. Acad. Sci. 2010, 1187, 4– 34, DOI: 10.1111/j.1749-6632.2009.05149.x[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXks1Snurc%253D&md5=48ded12d27f36b8d77717b118ccfa869Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disordersHeidbreder, Christian A.; Newman, Amy H.Annals of the New York Academy of Sciences (2010), 1187 (Addiction Reviews 2), 4-34CODEN: ANYAA9; ISSN:0077-8923. (Wiley-Blackwell)A review. Repeated exposure to drugs of abuse produces long-term mol. and neurochem. changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing no. of new mol. and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D3 receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D3 receptor antagonists. Growing preclin. evidence indicates that these compds. may actually regulate the motivation to self-administer drugs and disrupt drug-assocd. cue-induced craving. This report will be divided into three parts. First, preclin. evidence in support of the efficacy of selective DA D3 receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D2/D3 receptor antagonists will not be discussed here because most of these compds. have low selectivity at the D3 vs. D2 receptor, and their efficacy profile is related primarily to functional antagonism at D2 receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chem. for the identification and optimization of selective DA D3 receptor antagonists and partial agonists will be analyzed. Third, translational research from preclin. efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed.
- 65Banala, A. K.; Levy, B. A.; Khatri, S. S.; Furman, C. A.; Roof, R. A.; Mishra, Y.; Griffin, S. A.; Sibley, D. R.; Luedtke, R. R.; Newman, A. H. N-(3-fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as selective dopamine D3 receptor ligands: critical role of the carboxamide linker for D3 receptor selectivity. J. Med. Chem. 2011, 54, 3581– 3594, DOI: 10.1021/jm200288r[ACS Full Text], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsVyhsbw%253D&md5=4fecff363e5628b365e7aeba6a824f9dN-(3-Fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as Selective Dopamine D3 Receptor Ligands: Critical Role of the Carboxamide Linker for D3 Receptor SelectivityBanala, Ashwini K.; Levy, Benjamin A.; Khatri, Sameer S.; Furman, Cheryse A.; Roof, Rebecca A.; Mishra, Yogesh; Griffin, Suzy A.; Sibley, David R.; Luedtke, Robert R.; Newman, Amy HauckJournal of Medicinal Chemistry (2011), 54 (10), 3581-3594CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)N-(3-Fluoro-4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)arylcarboxamides were prepd. and evaluated for binding and function at dopamine D3 receptors (D3Rs) and dopamine D2 receptors (D2Rs). In this series, we discovered some of the most D3R selective compds. reported to date (e.g., I, >1000-fold D3R-selective over D2R). In addn., chimeric receptor studies further identified the second extracellular (E2) loop as an important contributor to D3R binding selectivity. Further, compds. lacking the carbonyl group in the amide linker were synthesized, and while these amine-linked analogs bound with similar affinities to the amides at D2R, this modification dramatically reduced binding affinities at D3R by >100-fold, resulting in compds. with significantly reduced D3R selectivity. This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compds. and further reveals a point of sepn. between structure-activity relationships at D3R and D2R.
- 66Keck, T. M.; Banala, A. K.; Slack, R. D.; Burzynski, C.; Bonifazi, A.; Okunola-Bakare, O. M.; Moore, M.; Deschamps, J. R.; Rais, R.; Slusher, B. S.; Newman, A. H. Using click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligands. Bioorg. Med. Chem. 2015, 23, 4000– 4012, DOI: 10.1016/j.bmc.2015.01.017[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Oju7w%253D&md5=d35aea3134fe53f9d5bea86519ce6e8fUsing click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligandsKeck, Thomas M.; Banala, Ashwini K.; Slack, Rachel D.; Burzynski, Caitlin; Bonifazi, Alessandro; Okunola-Bakare, Oluyomi M.; Moore, Martin; Deschamps, Jeffrey R.; Rais, Rana; Slusher, Barbara S.; Hauck Newman, AmyBioorganic & Medicinal Chemistry (2015), 23 (14), 4000-4012CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)The dopamine D3 receptor (D3R) is a target of pharmacotherapeutic interest in a variety of neurol. disorders including schizophrenia, Parkinson's disease, restless leg syndrome, and drug addiction. A common mol. template used in the development of D3R-selective antagonists and partial agonists incorporates a butylamide linker between two pharmacophores, a phenylpiperazine moiety and an extended aryl ring system. The series of compds. described herein incorporates a change to that chem. template, replacing the amide functional group in the linker chain with a 1,2,3-triazole group. Although the amide linker in the 4-phenylpiperazine class of D3R ligands has been previously deemed crit. for high D3R affinity and selectivity, the 1,2,3-triazole moiety serves as a suitable bioisosteric replacement and maintains desired D3R-binding functionality of the compds. Addnl., using mouse liver microsomes to evaluate CYP450-mediated phase I metab., the authors detd. that novel 1,2,3-triazole-contg. compds. modestly improves metabolic stability compared to amide-contg. analogs. The 1,2,3-triazole moiety allows for the modular attachment of chem. subunit libraries using copper-catalyzed azide-alkyne cycloaddn. click chem., increasing the range of chem. entities that can be designed, synthesized, and developed toward D3R-selective therapeutic agents.
- 67Appendino, G.; Bacchiega, S.; Minassi, A.; Cascio, M. G.; De Petrocellis, L.; Di Marzo, V. The 1,2,3-triazole ring as a peptido- and olefinomimetic element: discovery of click vanilloids and cannabinoids. Angew. Chem., Int. Ed. 2007, 46, 9312– 9315, DOI: 10.1002/anie.200703590[Crossref], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhslWksg%253D%253D&md5=7b74f7fce4f8462cc61822eb4d52bb83The 1,2,3-triazole ring as a peptido- and olefinomimetic element: discovery of click vanilloids and cannabinoidsAppendino, Giovanni; Bacchiega, Sara; Minassi, Alberto; Cascio, Maria Grazia; De Petrocellis, Luciano; Di Marzo, VincenzoAngewandte Chemie, International Edition (2007), 46 (48), 9312-9315CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Fooling nature: The replacement of amide and alkene groups in a biol. setting with the 1,2,3-triazole group led to the discovery of compds. with a unique vanilloid/cannabinoid mixed profile. For example, the natural amides (see picture, above) and their triazole mimics (below) exhibit similar agonistic (X = H) or antagonistic (X = I) activity towards the TRPV1 receptor; however, only the triazole derivs. also show cannabinomimetic activity.
- 68Mugnaini, C.; Nocerino, S.; Pedani, V.; Pasquini, S.; Tafi, A.; De Chiaro, M.; Bellucci, L.; Valoti, M.; Guida, F.; Luongo, L.; Dragoni, S.; Ligresti, A.; Rosenberg, A.; Bolognini, D.; Cascio, M. G.; Pertwee, R. G.; Moaddel, R.; Maione, S.; Di Marzo, V.; Corelli, F. Investigations on the 4-quinolone-3-carboxylic acid motif part 5: modulation of the physicochemical profile of a set of potent and selective cannabinoid-2 receptor ligands through a bioisosteric approach. ChemMedChem 2012, 7, 920– 934, DOI: 10.1002/cmdc.201100573[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtFOhtbo%253D&md5=4ac67390a8af749cd21afd9ef894099fInvestigations on the 4-Quinolone-3-Carboxylic Acid Motif Part 5: Modulation of the Physicochemical Profile of a Set of Potent and Selective Cannabinoid-2 Receptor Ligands through a Bioisosteric ApproachMugnaini, Claudia; Nocerino, Stefania; Pedani, Valentina; Pasquini, Serena; Tafi, Andrea; De Chiaro, Maria; Bellucci, Luca; Valoti, Massimo; Guida, Francesca; Luongo, Livio; Dragoni, Stefania; Ligresti, Alessia; Rosenberg, Avraham; Bolognini, Daniele; Cascio, Maria Grazia; Pertwee, Roger G.; Moaddel, Ruin; Maione, Sabatino; Di Marzo, Vincenzo; Corelli, FedericoChemMedChem (2012), 7 (5), 920-934CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Three heterocyclic systems were selected as potential bioisosteres of the amide linker for a series of 1,6-disubstituted-4-quinolone-3-carboxamides, which are potent and selective CB2 ligands that exhibit poor water soly., with the aim of improving their physicochem. profile and also of clarifying properties of importance for amide bond mimicry. Among the newly synthesized compds., a 1,2,3-triazole deriv. (1-(adamantan-1-yl)-4-[6-(furan-2-yl)-1,4-dihydro-4-oxo-1-pentylquinolin-3-yl]-1H-1,2,3-triazole) emerged as the most promising in terms of both physicochem. and pharmacodynamic properties. When assayed in vitro, this deriv. exhibited inverse agonist activity, whereas, in the formalin test in mice, it produced analgesic effects antagonized by a well-established inverse agonist. Metabolic studies allowed the identification of a side chain hydroxylated deriv. as its only metabolite, which, in its racemic form, still showed appreciable CB2 selectivity, but was 150-fold less potent than the parent compd.
- 69Cabral, G. A.; Griffin-Thomas, L. Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev. Mol. Med. 2009, 11, e3, DOI: 10.1017/S1462399409000957
- 70Dhopeshwarkar, A.; Mackie, K. CB2 Cannabinoid receptors as a therapeutic target-what does the future hold?. Mol. Pharmacol. 2014, 86, 430– 437, DOI: 10.1124/mol.114.094649[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs12iu7nN&md5=76d3335b4ef5194f805f67619466739bCB2 cannabinoid receptors as a therapeutic target - what does the future hold?Dhopeshwarkar, Amey; Mackie, KenMolecular Pharmacology (2014), 86 (4), 430-437, 8 pp.CODEN: MOPMA3; ISSN:1521-0111. (American Society for Pharmacology and Experimental Therapeutics)A review. The past decades have seen an exponential rise in our understanding of the endocannabinoid system, comprising CB1 and CB2 cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that synthesize and degrade endocannabinoids. The primary focus of this review is the CB2 receptor. CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential for treating various pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor-based therapies. With the appreciation that CB2-selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research from both a mechanistic as well as a therapeutic perspective. In this review, we summarize our present knowledge of CB2 receptor signaling, localization, and regulation. We discuss the availability of genetic tools (and their limitations) to study CB2 receptors and also provide an update on preclin. data on CB2 agonists in pain models. Finally, we suggest possible reasons for the failure of CB2 ligands in clin. pain trials and offer possible ways to move the field forward in a way that can help reconcile the inconsistencies between preclin. and clin. data.
- 71Turcotte, C.; Blanchet, M. R.; Laviolette, M.; Flamand, N. The CB2 receptor and its role as a regulator of inflammation. Cell. Mol. Life Sci. 2016, 73, 4449– 4470, DOI: 10.1007/s00018-016-2300-4[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFCrtLrN&md5=572eaca44428863b1c69dde0bca87662The CB2 receptor and its role as a regulator of inflammationTurcotte, Caroline; Blanchet, Marie-Renee; Laviolette, Michel; Flamand, NicolasCellular and Molecular Life Sciences (2016), 73 (23), 4449-4470CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Basel)The CB2 receptor is the peripheral receptor for cannabinoids. It is mainly expressed in immune tissues, highlighting the possibility that the endocannabinoid system has an immunomodulatory role. In this respect, the CB2 receptor was shown to modulate immune cell functions, both in cellulo and in animal models of inflammatory diseases. In this regard, numerous studies have reported that mice lacking the CB2 receptor have an exacerbated inflammatory phenotype. This suggests that therapeutic strategies aiming at modulating CB2 signaling could be promising for the treatment of various inflammatory conditions. Herein, we review the pharmacol. of the CB2 receptor, its expression pattern, and the signaling pathways induced by its activation. We next examine the regulation of immune cell functions by the CB2 receptor and the evidence obtained from primary human cells, immortalized cell lines, and animal models of inflammation. Finally, we discuss the possible therapies targeting the CB2 receptor and the questions that remain to be addressed to det. whether this receptor could be a potential target to treat inflammatory disease.
- 72Koufaki, M.; Detsi, A.; Theodorou, E.; Kiziridi, C.; Calogeropoulou, T.; Vassilopoulos, A.; Kourounakis, A. P.; Rekka, E.; Kourounakis, P. N.; Gaitanaki, C.; Papazafiri, P. Synthesis of chroman analogues of lipoic acid and evaluation of their activity against reperfusion arrhythmias. Bioorg. Med. Chem. 2004, 12, 4835– 4841, DOI: 10.1016/j.bmc.2004.07.012[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXntFSntbk%253D&md5=4e935fc643ff40bd4aa134010e1018f8Synthesis of chroman analogues of lipoic acid and evaluation of their activity against reperfusion arrhythmiasKoufaki, Maria; Detsi, Anastasia; Theodorou, Elissavet; Kiziridi, Christina; Calogeropoulou, Theodora; Vassilopoulos, Athanasios; Kourounakis, Angeliki P.; Rekka, Eleni; Kourounakis, Panos N.; Gaitanaki, Catherine; Papazafiri, PanagiotaBioorganic & Medicinal Chemistry (2004), 12 (18), 4835-4841CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)Novel hybrids of lipoic acid and trolox connected through triamine spacers as well as analogs in which the lipoic acid was attached at different positions of the chroman moiety of vitamin E through an amide bond, were synthesized and exhibited strong inhibition of the microsomal lipid peroxidn. Moreover, the new mols., e.g., I, at 1 μM concn., reduced reperfusion arrhythmias and MDA content on isolated rat heart prepns., with the 2- and 5-substituted chromans possessing the better cardioprotective activity.
- 73Koufaki, M.; Kiziridi, C.; Alexi, X.; Alexis, M. N. Design and synthesis of novel neuroprotective 1,2-dithiolane/chroman hybrids. Bioorg. Med. Chem. 2009, 17, 6432– 6441, DOI: 10.1016/j.bmc.2009.07.010[Crossref], [PubMed], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVenur3J&md5=798070233784afcaf51b380ff14b00b9Design and synthesis of novel neuroprotective 1,2-dithiolane/chroman hybridsKoufaki, Maria; Kiziridi, Christina; Alexi, Xanthippi; Alexis, Michael N.Bioorganic & Medicinal Chemistry (2009), 17 (17), 6432-6441CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Novel 1,2-dithiolane/chroman hybrids bearing heterocyclic rings such as 1,2,4- and 1,3,4-oxadiazole, 1,2,3-triazole and tetrazole were designed and synthesized. The neuroprotective activity of the new analogs was tested against oxidative stress-induced cell death of glutamate-challenged HT22 hippocampal neurons. Our results show that bioisosteric replacement of amide group in 2-position of the chroman moiety, by 1,3,4-oxadiazole did not affect activity. However, analog 5 (I) bearing the 1,2,4-oxadiazole moiety showed improved neuroprotective activity. The presence of nitrogen heterocycles strongly influences the neuroprotective activity of 5-substituted chroman derivs., depending on the nature of heterocycle. Replacement of the amide group of the first generation analogs by 1,2,4-oxadiazole or 1,2,3-triazole resulted in significant improvement of the activity against glutamate induced oxidative stress.
- 74Koufaki, M.; Calogeropoulou, T.; Detsi, A.; Roditis, A.; Kourounakis, A. P.; Papazafiri, P.; Tsiakitzis, K.; Gaitanaki, C.; Beis, I.; Kourounakis, P. N. Novel potent inhibitors of lipid peroxidation with protective effects against reperfusion arrhythmias. J. Med. Chem. 2001, 44, 4300– 4303, DOI: 10.1021/jm010962w[ACS Full Text], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnvVOjs78%253D&md5=281895d241c853441bf368a5291e06beNovel Potent Inhibitors of Lipid Peroxidation with Protective Effects against Reperfusion ArrhythmiasKoufaki, Maria; Calogeropoulou, Theodora; Detsi, Anastasia; Roditis, Aristidis; Kourounakis, Angeliki P.; Papazafiri, Panagiota; Tsiakitzis, Karyofyllis; Gaitanaki, Catherine; Beis, Isidoros; Kourounakis, Panos N.Journal of Medicinal Chemistry (2001), 44 (24), 4300-4303CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of new compds. that contain lipoic acid and trolox connected through spacers were synthesized and examd. for their antioxidant activity and their protective effects against reperfusion arrhythmias in isolated heart prepns. All compds. tested are strong inhibitors of lipid peroxidn. in rat liver microsomal membranes induced by ferrous ions and ascorbate. N-(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carbonyl)-N'-(1,2-dithiolane-3-pentanoyl)-1,2-phenylenediamine (I) exhibits anti-lipid peroxidn. activity at the nanomolar range. N-(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carbonyl)-N'-(1,2-dithiolane-3-pentanoyl)ethylenediamine (II) and I totally suppressed reperfusion arrhythmias.
- 75Rosini, M.; Andrisano, V.; Bartolini, M.; Bolognesi, M. L.; Hrelia, P.; Minarini, A.; Tarozzi, A.; Melchiorre, C. Rational approach to discover multipotent anti-Alzheimer drugs. J. Med. Chem. 2005, 48, 360– 363, DOI: 10.1021/jm049112h[ACS Full Text], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjslSk&md5=e632c934e744d35d5acf7047827fc91fRational Approach To Discover Multipotent Anti-Alzheimer DrugsRosini, Michela; Andrisano, Vincenza; Bartolini, Manuela; Bolognesi, Maria L.; Hrelia, Patrizia; Minarini, Anna; Tarozzi, Andrea; Melchiorre, CarloJournal of Medicinal Chemistry (2005), 48 (2), 360-363CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The coupling of two different pharmacophores, each endowed with different biol. properties, afforded the hybrid compd. lipocrine (7), whose biol. profile was markedly improved relative to those of prototypes tacrine and lipoic acid. Lipocrine is the first compd. that inhibits the catalytic activity of AChE and AChE-induced amyloid-β aggregation and protects against reactive oxygen species. Thus, it emerged as a valuable pharmacol. tool to investigate Alzheimer's disease and as a promising lead compd. for new anti-Alzheimer drugs.
- 76Maczurek, A.; Shanmugam, K.; Munch, G. Inflammation and the redox-sensitive AGE-RAGE pathway as a therapeutic target in Alzheimer’s disease. Ann. N. Y. Acad. Sci. 2008, 1126, 147– 151, DOI: 10.1196/annals.1433.026[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmtFygu74%253D&md5=a663abce366feec4856af9ab830c9bc8Inflammation and the redox-sensitive AGE-RAGE pathway as a therapeutic target in Alzheimer's diseaseMaczurek, Annette; Shanmugam, Kirubakaran; Muench, GeraldAnnals of the New York Academy of Sciences (2008), 1126 (Maillard Reaction), 147-151CODEN: ANYAA9; ISSN:0077-8923. (Blackwell Publishing, Inc.)A review. Alzheimer's disease (AD) is the most common cause of dementia. Neuritic amyloid plaques and concomitant chronic inflammation are prominent pathol. features of AD. β-Amyloid peptide (Aβ), the major component of plaques, and advanced glycation end products (AGEs), post-translational protein modifications, are key activators of plaque-assocd. inflammation. Aβ, AGEs, S100b, and amphoterin bind to the receptor for AGEs (RAGE), which transmits the signal from RAGE via redox-sensitive pathways to nuclear factor kappa-B (NF-κB)-regulated cytokines. RAGE-mediated inflammation caused by glial cells and subsequent changes in neuronal glucose metab. are likely to be important contributors to neurodegeneration in AD. As long as the neuronal damage is reversible, drugs interfering with the Aβ and AGE-RAGE pathways might be interesting novel therapeutics for the treatment of AD.
- 77Harnett, J. J.; Auguet, M.; Viossat, I.; Dolo, C.; Bigg, D.; Chabrier, P. E. Novel lipoic acid analogues that inhibit nitric oxide synthase. Bioorg. Med. Chem. Lett. 2002, 12, 1439– 1442, DOI: 10.1016/S0960-894X(02)00216-0[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xjsl2lt7o%253D&md5=d85be5192fe6216a7159d3610636ab0aNovel lipoic acid analogues that inhibit nitric oxide synthaseHarnett, Jeremiah J.; Auguet, Michel; Viossat, Isabelle; Dolo, Christine; Bigg, Dennis; Chabrier, Pierre-E.Bioorganic & Medicinal Chemistry Letters (2002), 12 (11), 1439-1442CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The synthesis and biol. activity of novel lipoic acid analogs, e.g. I, are reported. Lipoic acid and structural homologs coupled to arylthiophene amidine via carboxamide linkers are metabolic antioxidants capable of protecting neuronal cells against glutamate cytotoxicity, preventing loss of intracellular glutathione, and inhibit nitric oxide synthase.
- 78Dozio, E.; Ruscica, M.; Passafaro, L.; Dogliotti, G.; Steffani, L.; Marthyn, P.; Pagani, A.; Demartini, G.; Esposti, D.; Fraschini, F.; Magni, P. The natural antioxidant alpha-lipoic acid induces p27(Kip1)-dependent cell cycle arrest and apoptosis in MCF-7 human breast cancer cells. Eur. J. Pharmacol. 2010, 641, 29– 34, DOI: 10.1016/j.ejphar.2010.05.009[Crossref], [PubMed], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvVyjsLw%253D&md5=a76d8959f22aab4e35078a95270ba5f0The natural antioxidant alpha-lipoic acid induces p27Kip1-dependent cell cycle arrest and apoptosis in MCF-7 human breast cancer cellsDozio, Elena; Ruscica, Massimiliano; Passafaro, Luca; Dogliotti, Giada; Steffani, Liliana; Pagani, Alessandra; Demartini, Germana; Esposti, Daniele; Fraschini, Franco; Magni, PaoloEuropean Journal of Pharmacology (2010), 641 (1), 29-34CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)Unlike normal cells, tumor cells survive in a specific redox environment where the elevated reactive oxygen species contribute to enhance cell proliferation and to suppress apoptosis. Alpha-lipoic acid, a naturally occurring reactive oxygen species scavenger, has been shown to possess anticancer activity, due to its ability to suppress proliferation and to induce apoptosis in different cancer cell lines. Since at the moment little information is available regarding the potential effects of alpha-lipoic acid on breast cancer, in the present study we addressed the question whether alpha-lipoic acid induces cell cycle arrest and apoptosis in the human breast cancer cell line MCF-7. Moreover, we investigated some mol. mechanisms which mediate alpha-lipoic acid actions, focusing on the role of the PI3-K/Akt signaling pathway. We obsd. that alpha-lipoic acid is able to scavenge reactive oxygen species in MCF-7 cells and that the redn. of reactive oxygen species is followed by cell growth arrest in the G1 phase of the cell cycle, via the specific inhibition of Akt pathway and the up-regulation of the cyclin-dependent kinase inhibitor p27kip1, and by apoptosis, via changes of the ratio of the apoptotic-related protein Bax/Bcl-2. Thus, the antitumor activity of alpha-lipoic acid obsd. in MCF-7 cells further stresses the role of redox state in regulating cancer initiation and progression.
- 79Zhang, S. J.; Ge, Q. F.; Guo, D. W.; Hu, W. X.; Liu, H. Z. Synthesis and anticancer evaluation of α-lipoic acid derivatives. Bioorg. Med. Chem. Lett. 2010, 20, 3078– 3083, DOI: 10.1016/j.bmcl.2010.03.112[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlsFGns78%253D&md5=3bd63422925179c5de11e4bad4e7dcd7Synthesis and anticancer evaluation of α-lipoic acid derivativesZhang, Shi-Jie; Ge, Qiu-Fu; Guo, Dian-Wu; Hu, Wei-Xiao; Liu, Hua-ZhangBioorganic & Medicinal Chemistry Letters (2010), 20 (10), 3078-3083CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)α-Lipoic acid derivs. were synthesized and evaluated for their in vitro anticancer activities against NCI-460, HO-8910, KB, BEL-7402, and PC-3 cell lines. The results, for most compds. exhibited dose-dependent inhibitory property and several compds. had good inhibitions at the dose of 100 μg/mL. Compd. I was further selected for in vivo evaluation against S180 xenograft in ICR mice, which had 24.7% tumor-wt. inhibition through intragastric administration of 200 mg/kg of body wt. Moreover, the LD50 in mice for I through ig exceeded 1000 mg/kg of body wt.
- 80Dorsam, B.; Fahrer, J. The disulfide compound α-lipoic acid and its derivatives: a novel class of anticancer agents targeting mitochondria. Cancer Lett. 2016, 371, 12– 19, DOI: 10.1016/j.canlet.2015.11.019[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28vltVOrtg%253D%253D&md5=46d83c0e531c0482b4c932ac50af950fThe disulfide compound α-lipoic acid and its derivatives: A novel class of anticancer agents targeting mitochondriaDorsam Bastian; Fahrer JorgCancer letters (2016), 371 (1), 12-9 ISSN:.The endogenous disulfide α-lipoic acid (LA) is an essential mitochondrial co-factor. In addition, LA and its reduced counterpart dihydro lipoic acid form a potent redox couple with antioxidative functions, for which it is used as dietary supplement and therapeutic. Recently, it has gained attention due to its cytotoxic effects in cancer cells, which is the key aspect of this review. We initially recapitulate the dietary occurrence, gastrointestinal absorption and pharmacokinetics of LA, illustrating its diverse antioxidative mechanisms. We then focus on its mode of action in cancer cells, in which it triggers primarily the mitochondrial pathway of apoptosis, whereas non-transformed primary cells are hardly affected. Furthermore, LA impairs oncogenic signaling and displays anti-metastatic potential. Novel LA derivatives such as CPI-613, which target mitochondrial energy metabolism, are described and recent pre-clinical studies are presented, which demonstrate that LA and its derivatives exert antitumor activity in vivo. Finally, we highlight clinical studies currently performed with the LA analog CPI-613. In summary, LA and its derivatives are promising candidates to complement the arsenal of established anticancer drugs due to their mitochondria-targeted mode of action and non-genotoxic properties.
- 81Melagraki, G.; Afantitis, A.; Igglessi-Markopoulou, O.; Detsi, A.; Koufaki, M.; Kontogiorgis, C.; Hadjipavlou-Litina, D. J. Synthesis and evaluation of the antioxidant and anti-inflammatory activity of novel coumarin-3-aminoamides and their alpha-lipoic acid adducts. Eur. J. Med. Chem. 2009, 44, 3020– 3026, DOI: 10.1016/j.ejmech.2008.12.027[Crossref], [PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXltl2lur8%253D&md5=d3cbd828bc9bcea1cccde86061fe699fSynthesis and evaluation of the antioxidant and anti-inflammatory activity of novel coumarin-3-aminoamides and their alpha-lipoic acid adductsMelagraki, Georgia; Afantitis, Antreas; Igglessi-Markopoulou, Olga; Detsi, Anastasia; Koufaki, Maria; Kontogiorgis, Christos; Hadjipavlou-Litina, Dimitra J.European Journal of Medicinal Chemistry (2009), 44 (7), 3020-3026CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)In the present work a series of novel coumarin-3-carboxamides, i.e. I, and their hybrids with the alpha-lipoic acid were designed, synthesized and tested as potent antioxidant and anti-inflammatory agents. The new compds. were evaluated for their antioxidant activity, their activity to inhibit in vitro lipoxygenase and their in vivo anti-inflammatory activity. In general, the derivs. were generally found to present antioxidant and anti-inflammatory activities. Discussion is made based on the results for the structure-activity relationships in order to define the structural features required for activity.
- 82Chouinard, G. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J. Clin. Psychiatry 2004, 65 (Suppl. 5), 7– 12[PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjslGqsLs%253D&md5=04d90f92ddd14af6c805b2bf57c54c13Issues in the clinical use of benzodiazepines: Potency, withdrawal, and reboundChouinard, GuyJournal of Clinical Psychiatry (2004), 65 (Suppl. 5), 7-12CODEN: JCLPDE; ISSN:0160-6689. (Physicians Postgraduate Press, Inc.)A review. Low and medium potency benzodiazepines were initially introduced for the treatment of insomnia and anxiety. Their therapeutic actions as anxiolytics, sedative hypnotics, anticonvulsants, and muscle relaxants (with their low toxicity) have led to their use as first-line treatments, and they have become one of the most prescribed classes of drugs. Novel therapeutic uses of benzodiazepines were discovered with the introduction of the high-potency benzodiazepines (e.g., alprazolam, clonazepam, and lorazepam). They were found to be effective in treating panic disorder and panic attacks with or without agoraphobia, as add-on therapy to selective serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder and panic disorders, and as adjunctive therapy in treating patients with acute mania or acute agitation. High-potency benzodiazepines have replaced low and medium potency benzodiazepines in all benzodiazepine clin. indications due to their greater therapeutic effects and rapid onset of action. Differences in distribution, elimination half-life, and rate of absorption are important considerations when choosing a high-potency benzodiazepine. Typically, a benzodiazepine with long distribution and elimination half-lives is preferred. A max. dose of 2 mg/day of any of the high-potency benzodiazepines when given for more than 1 wk is recommended. Although as a class benzodiazepines act rapidly and are well tolerated, their use presents clin. issues such as dependence, rebound anxiety, memory impairment, and discontinuation syndrome.
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- 84Hershon, H. I.; Parsonage, M. Comparative trial of diazepam and pheneturide in treatment of epilepsy. Lancet 1969, 294, 859– 862, DOI: 10.1016/S0140-6736(69)92324-1
- 85Robinson, G. M.; Sellers, E. M. Diazepam withdrawal seizures. Can. Med. Assoc. J. 1982, 126, 944– 945[PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL387otl2rtg%253D%253D&md5=b9b8ed8316d829536001e54cac547e05Diazepam withdrawal seizuresRobinson G M; Sellers E MCanadian Medical Association journal (1982), 126 (8), 944-5 ISSN:0008-4409.There is no expanded citation for this reference.
- 86Devenyi, P.; Harrison, M. L. Prevention of alcohol withdrawal seizures with oral diazepam loading. Can. Med. Assoc. J. 1985, 132, 798– 800[PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M7ltFCmsQ%253D%253D&md5=018cf5c7d636492a064dc985a60d2010Prevention of alcohol withdrawal seizures with oral diazepam loadingDevenyi P; Harrison M LCanadian Medical Association journal (1985), 132 (7), 798-800 ISSN:0008-4409.Twenty patients withdrawing from alcohol who had reliable histories of previous alcohol-withdrawal seizures and thus were at high risk for a subsequent seizure were treated in hospital with oral diazepam loading: 20 mg of the drug was given every hour to a minimum total of 60 mg. None of the patients had a seizure during the stay in hospital. We believe that phenytoin prophylaxis is not necessary in these circumstances. However, if the patient is already taking phenytoin, this drug should not be abruptly discontinued in the withdrawal period in favour of diazepam loading.
- 87Griffin, C. E., 3rd; Kaye, A. M.; Bueno, F. R.; Kaye, A. D. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013, 13, 214– 223[PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sjktlGjsw%253D%253D&md5=c052a8d07f0a07afb4cd42e946a3d3e4Benzodiazepine pharmacology and central nervous system-mediated effectsGriffin Charles E 3rd; Kaye Adam M; Bueno Franklin Rivera; Kaye Alan DThe Ochsner journal (2013), 13 (2), 214-23 ISSN:1524-5012.BACKGROUND: Owing to the low therapeutic index of barbiturates, benzodiazepines (BZDs) became popular in this country and worldwide many decades ago for a wide range of conditions. Because of an increased understanding of pharmacology and physiology, the mechanisms of action of many BZDs are now largely understood, and BZDs of varying potency and duration of action have been developed and marketed. Although BZDs have many therapeutic roles and BZD-mediated effects are typically well tolerated in the general population, side effects and toxicity can result in morbidity and mortality for some patients. The elderly; certain subpopulations of patients with lung, liver, or kidney dysfunction; and patients on other classes of medication are especially prone to toxicity. METHODS: This review details the present knowledge about BZD mechanisms of action, drug profiles, clinical actions, and potential side effects. In addition, this review describes numerous types of BZD-mediated central nervous system effects. CONCLUSION: For any patient taking a BZD, the prescribing physician must carefully evaluate the risks and benefits, and higher-risk patients require careful considerations. Clinically appropriate use of BZDs requires prudence and the understanding of pharmacology.
- 88Calcaterra, N. E.; Barrow, J. C. Classics in chemical neuroscience: diazepam (valium). ACS Chem. Neurosci. 2014, 5, 253– 260, DOI: 10.1021/cn5000056[ACS Full Text], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXis1entr0%253D&md5=0eb7cdab939d38e4eae78714825a495cClassics in Chemical Neuroscience: Diazepam (Valium)Calcaterra, Nicholas E.; Barrow, James C.ACS Chemical Neuroscience (2014), 5 (4), 253-260CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)A review. Diazepam (Valium) is among the most successful drugs from the onset of the psychopharmacol. revolution that began during the 1950s. Efficacious in treating a wide-spectrum of CNS disorders, including anxiety and epilepsy, it set the std. for pharmacotherapy in terms of potency, onset of action, and safety. In this Review, the legacy of diazepam to chem. neuroscience will be considered along with its synthesis, pharmacol., drug metab., adverse events and dependence, clin. use, and regulatory issues.
- 89Hester, J. B., Jr.; Rudzik, A. D.; Kamdar, B. V. 6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines which have central nervous system depressant activity. J. Med. Chem. 1971, 14, 1078– 1081, DOI: 10.1021/jm00293a015[ACS Full Text], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE38Xkt1Snsg%253D%253D&md5=aac07d19e5f37e7327c4e0f5e7855ba86-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines which have central nervous system depressant activityHester, Jackson B., Jr.; Rudzik, Allan D.; Kamdar, Bharat V.Journal of Medicinal Chemistry (1971), 14 (11), 1078-81CODEN: JMCMAR; ISSN:0022-2623.Seventeen 6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines (I) were prepd. by the reaction of 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thiones with carboxylic acid hydrazides. Pharmacol. testing in mice showed that this series had high central depressant activity with low concomitant toxicity. 1-Methyl-6-(o-chlorophenyl)-8-nitro-4H-s-triazolo[4,3-a][1,4]benzodiazepine [33887-02-4] (I, R = Me, R1 = Cl, R2 = H, R3 = NO2) was the most active compd. in the series, being effective in many tests in central depressant activity at doses < 10 μg/kg.
- 90Verster, J. C.; Volkerts, E. R. Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literature. CNS Drug Rev. 2004, 10, 45– 76, DOI: 10.1111/j.1527-3458.2004.tb00003.x[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjtlClu7c%253D&md5=6db5034044ff02a6782b6a132da82062Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literatureVerster, Joris C.; Volkerts, Edmund R.CNS Drug Reviews (2004), 10 (1), 45-76CODEN: CDREFB; ISSN:1080-563X. (Neva Press)A review. Alprazolam is a benzodiazepine deriv. that is currently used in the treatment of generalized anxiety, panic attacks with or without agoraphobia, and depression. Alprazolam has a fast onset of symptom relief (within the first week); it is unlikely to produce dependency or abuse. No tolerance to its therapeutic effect has been reported. At discontinuation of alprazolam treatment, withdrawal and rebound symptoms are common. Hence, alprazolam discontinuation must be tapered. An exhaustive review of the literature showed that alprazolam is significantly superior to placebo, and is at least equally effective in the relief of symptoms as tricyclic antidepressants (TCAs), such as imipramine. However, although alprazolam and imipramine are significantly more effective than placebo in the treatment of panic attacks, Selective Serotonin Reuptake Inhibitors (SSRIs) appear to be superior to either of the two drugs. Therefore, alprazolam is recommended as a second line treatment option, when SSRIs are not effective or well tolerated. In addn. to its therapeutic effects, alprazolam produces adverse effects, such as drowsiness and sedation. Since alprazolam is widely used, many clin. studies investigated its cognitive and psychomotor effects. It is evident from these studies that alprazolam may impair performance in a variety of skills in healthy volunteers as well as in patients. Since the majority of alprazolam users are outpatients, this behavioral impairment limits the safe use of alprazolam in patients routinely engaged in potentially dangerous daily activities, such as driving a car.
- 91de Oliveira, C. S.; Lira, B. F.; Barbosa-Filho, J. M.; Lorenzo, J. G.; de Athayde-Filho, P. F. Synthetic approaches and pharmacological activity of 1,3,4-oxadiazoles: a review of the literature from 2000–2012. Molecules 2012, 17, 10192– 10231, DOI: 10.3390/molecules170910192[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bhslSjsA%253D%253D&md5=4f09fb45888e071f2601ff846fc83d9dSynthetic approaches and pharmacological activity of 1,3,4-oxadiazoles: a review of the literature from 2000-2012de Oliveira Cledualdo Soares; Lira Bruno Freitas; Barbosa-Filho Jose Maria; Lorenzo Jorge Goncalo Fernandez; de Athayde-Filho Petronio FilgueirasMolecules (Basel, Switzerland) (2012), 17 (9), 10192-231 ISSN:.This review provides readers with an overview of the main synthetic methodologies for 1,3,4-oxadiazole derivatives, and of their broad spectrum of pharmacological activities as reported over the past twelve years.
- 92Bostrom, J.; Hogner, A.; Llinas, A.; Wellner, E.; Plowright, A. T. Oxadiazoles in medicinal chemistry. J. Med. Chem. 2012, 55, 1817– 1830, DOI: 10.1021/jm2013248[ACS Full Text], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC383pt1Oisw%253D%253D&md5=b934995431ced1be297e6f126262f3cbOxadiazoles in medicinal chemistryBostrom Jonas; Hogner Anders; Llinas Antonio; Wellner Eric; Plowright Alleyn TJournal of medicinal chemistry (2012), 55 (5), 1817-30 ISSN:.Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and amide functionalities. The current study presents a systematic comparison of 1,2,4- and 1,3,4-oxadiazole matched pairs in the AstraZeneca compound collection. In virtually all cases, the 1,3,4-oxadiazole isomer shows an order of magnitude lower lipophilicity (log D), as compared to its isomeric partner. Significant differences are also observed with respect to metabolic stability, hERG inhibition, and aqueous solubility, favoring the 1,3,4-oxadiazole isomers. The difference in profile between the 1,2,4 and 1,3,4 regioisomers can be rationalized by their intrinsically different charge distributions (e.g., dipole moments). To facilitate the use of these heteroaromatic rings, novel synthetic routes for ready access of a broad spectrum of 1,3,4-oxadiazoles, under mild conditions, are described.
- 93Cao, Y.; Min, C.; Acharya, S.; Kim, K. M.; Cheon, S. H. Design, synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligands. Bioorg. Med. Chem. 2016, 24, 191– 200, DOI: 10.1016/j.bmc.2015.12.002[Crossref], [PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVKju7%252FE&md5=75a979afabeb9b2fc0c30e06eea74672Design, synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligandsCao, Yongkai; Min, Chengchun; Acharya, Srijan; Kim, Kyeong-Man; Cheon, Seung HoonBioorganic & Medicinal Chemistry (2016), 24 (2), 191-200CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)The dopamine D3 receptor (D3R) was proposed as a therapeutic target for drug development to treat drug abuse and addiction and neuropsychiatric disorders. Several D3R-selective modulators over the dopamine D2 receptor (D2R) can avoid extrapyramidal symptoms (EPS) and hyperprolactinemia. However, few biased D3R ligands were identified or showed a narrow range of selectivity at the D3R over D2R because of their high sequence homol. Herein, we designed, synthesized and evaluated the binding affinity of a series of bitopic ligands: arypiperazine-phenyl-1,2,4-oxadiazoles. Compd. 9e·HCl was the most potent and selective D3R modulator among these bitopic ligands. Mol. modeling revealed that D3R selectivity depends on the divergence of secondary binding pocket (SBP) in D3R and D2R. Specifically, non-conserved Tyr36, EL1 esp. non-conserved Thr92 and Gly94, and EL2 Val180, Cys181 and Ser182 of D3R may contribute to D3R specificity over D2R.
- 94Mashayekh, S.; Rahmanipour, N.; Mahmoodi, B.; Ahmadi, F.; Motaharian, D.; Shahhosseini, S.; Shafaroodi, H.; Banafshe, H. R.; Shafiee, A.; Navidpour, L. Synthesis, receptor affinity and effect on pentylenetetrazole-induced seizure threshold of novel benzodiazepine analogues: 3-substituted 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles and 2-amino-5-(phenoxybenzyl)-1,3,4-oxadiazoles. Bioorg. Med. Chem. 2014, 22, 1929– 1937, DOI: 10.1016/j.bmc.2014.01.041[Crossref], [PubMed], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisFeisLg%253D&md5=69937663049fafd998edff8b5264a515Synthesis, receptor affinity and effect on pentylenetetrazole-induced seizure threshold of novel benzodiazepine analogues: 3-Substituted 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles and 2-amino-5-(phenoxybenzyl)-1,3,4-oxadiazolesMashayekh, Siavash; Rahmanipour, Narges; Mahmoodi, Behnaz; Ahmadi, Fatemeh; Motaharian, Dina; Shahhosseini, Soraya; Shafaroodi, Hamed; Banafshe, Hamid R.; Shafiee, Abbas; Navidpour, LatifehBioorganic & Medicinal Chemistry (2014), 22 (6), 1929-1937CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)The new series of 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles I (R = SH, SMe, SEt, S-n-Pr, SCH2Ph, OEt, X = H, Cl, F, Y = Y, Cl), possessing C-3 thio, alkylthio and ethoxy substituents, and 2-amino-5-(2-phenoxybenzyl)-1,3,4-oxadiazoles II were designed and synthesized as novel benzodiazepine analogs. Most of them revealed similar to superior binding affinity to the GABAA/benzodiazepine receptor complex, relative to diazepam as the ref. drug. Among them, 5-[4-chloro-2-(2-fluorophenoxy)benzyl]-3-benzylthio-4H-1,2,4-triazole, I (R = SCH2Ph, X = F, Y = Cl), showed the highest affinity (IC50 = 0.892 nM) relative to diazepam (IC50 = 2.857 nM) and also showed the most increase in pentylenetetrazole-induced seizure threshold relative to diazepam as the ref. drug.
- 95Patel, S.; Freedman, S. B. The muscarinic receptor agonist L-658,903 modulates the in vivo accumulation of inositol monophosphates in mouse brain. Eur. J. Pharmacol., Mol. Pharmacol. Sect. 1994, 267, 329– 334, DOI: 10.1016/0922-4106(94)90158-9[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXkt1Kkt78%253D&md5=227f29d2872e8e1ce92b989631ccc1aaThe muscarinic receptor agonist L-658,903 modulates the in vivo accumulation of inositol monophosphates in mouse brainPatel, Shil; Freedman, Stephen B.European Journal of Pharmacology, Molecular Pharmacology Section (1994), 267 (3), 329-34CODEN: EJPPET; ISSN:0922-4106.In the present study the authors examd. the effects of lithium chloride and the muscarinic receptor agonists pilocarpine hydrochloride and L-658,903 (3-(3-methyl-1,2,4-oxadiazol-5-yl) quinuclidine hydrochloride) upon the accumulation of inositol monophosphates in mouse brain using a radiometric technique. Lithium was able to stimulate dose dependently the accumulation of inositol monophosphates with a minimal ED (MED) of 3 mEq/kg s.c. and maximal effect seen at 20 mEq/kg. This corresponded to an increase in the radioactivity in the inositol monophosphate fraction from 1.4±0.06% to 4.6±0.60%. The response was time-dependent, with a peak effect obsd. at 4 h post administration and returning to basal levels by 48 h. The muscarinic receptor agonist pilocarpine (MED 10 mg/kg i.p.) was able to enhance dose dependently the response to 10 mEq/kg lithium, with a max. response seen at 30 mg/kg (9.3% of the total brain radioactivity present in the inositol monophosphate fraction). The efficacious oxadiazole muscarinic receptor agonist L-658,903 also enhanced the response to lithium, producing a maximal effect of 10.4% of the total brain radioactivity present in the inositol monophosphate fraction at 1 mg/kg i.p. This stimulation was blocked by 1 mg/kg scopolamine i.p. but not by 1 mg/kg N-methylscopolamine. These results demonstrate the linkage of muscarinic receptors to the accumulation of inositol monophosphates in vivo, and confirm that following peripheral administration L-658,903 is a potent efficacious agonist at muscarinic receptors within the central nervous system.
- 96Maccioni, E.; Alcaro, S.; Cirilli, R.; Vigo, S.; Cardia, M. C.; Sanna, M. L.; Meleddu, R.; Yanez, M.; Costa, G.; Casu, L.; Matyus, P.; Distinto, S. 3-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles: a new scaffold for the selective inhibition of monoamine oxidase B. J. Med. Chem. 2011, 54, 6394– 6398, DOI: 10.1021/jm2002876[ACS Full Text], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVegt7zP&md5=0ebf27c64e591293045768508dd61ef83-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles: A new scaffold for the selective inhibition of monoamine oxidase BMaccioni, Elias; Alcaro, Stefano; Cirilli, Roberto; Vigo, Sara; Cardia, Maria Cristina; Sanna, Maria Luisa; Meleddu, Rita; Yanez, Matilde; Costa, Giosue; Casu, Laura; Matyus, Peter; Distinto, SimonaJournal of Medicinal Chemistry (2011), 54 (18), 6394-6398CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)3-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles e. g., I were designed, synthesized, and tested as inhibitors against human monoamine oxidase (MAO) A and B isoforms. Several compds., obtained as racemates, were identified as selective MAO-B inhibitors. The enantiomers of some derivs. were sepd. by enantioselective HPLC and tested. The R-enantiomers always showed the highest activity. Docking study and mol. dynamic simulations demonstrated the putative binding mode. We conclude that these 1,3,4-oxadiazoles derivs. are promising reversible and selective MAO-B inhibitors.
- 97Shook, B. C.; Jackson, P. F. Adenosine A(2A) receptor antagonists and Parkinson’s disease. ACS Chem. Neurosci. 2011, 2, 555– 567, DOI: 10.1021/cn2000537[ACS Full Text], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXosVSrsrc%253D&md5=81746259f96dd1a270f12c3cb2dbe1d3Adenosine A2A Receptor Antagonists and Parkinson's DiseaseShook, Brian C.; Jackson, Paul F.ACS Chemical Neuroscience (2011), 2 (10), 555-567CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)This Review summarizes and updates the work on adenosine A2A receptor antagonists for Parkinson's disease from 2006 to the present. There have been numerous publications, patent applications, and press releases within this time frame that highlight new medicinal chem. approaches to this attractive and promising target to treat Parkinson's disease. The Review is broken down by scaffold type and will discuss the efforts to optimize particular scaffolds for activity, pharmacokinetics, and other drug discovery parameters. The majority of approaches focus on prepg. selective A2A antagonists, but a few approaches to dual A2A/A1 antagonists will also be highlighted. The in vivo profiles of compds. will be highlighted and discussed to compare activities across different chem. series. A clin. report and update will be given on compds. that have entered clin. trials.
- 98Swain, C. J.; Baker, R.; Kneen, C.; Moseley, J.; Saunders, J.; Seward, E. M.; Stevenson, G.; Beer, M.; Stanton, J.; Watling, K. Novel 5-HT3 antagonists. indole oxadiazoles. J. Med. Chem. 1991, 34, 140– 151, DOI: 10.1021/jm00105a021[ACS Full Text], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXkt1Kksg%253D%253D&md5=08f7878a7b8d843a7518288fe4ac7e15Novel 5-HT3 antagonists. Indole oxadiazolesSwain, C. J.; Baker, R.; Kneen, C.; Moseley, J.; Saunders, J.; Seward, E. M.; Stevenson, G.; Beer, M.; Stanton, J.; Watling, K.Journal of Medicinal Chemistry (1991), 34 (1), 140-51CODEN: JMCMAR; ISSN:0022-2623.The synthesis and biochem. evaluation of a series of oxadiazole and indolyloxadiazole 5-HT3 (hydroxytryptamine) antagonists are described. The key pharmacophoric elements have been defined as a basic nitrogen, a linking group capable of H-bonding interactions, and an arom. moiety. The steric limitations of the arom. binding site have been detd. by substitution about the indole ring. Variation of the heterocyclic linking group has shown that while 2 H-bonding interactions are possible, only 1 is essential for high affinity. The environment of the basic nitrogen has been investigated and shown to be optimal when constrained within an azabicyclic system. These results have been incorporated into a proposed binding model for the 5-HT3 antagonist binding site, in which the optimum distance between the arom. binding site and the basic amine is 8.4-8.9 Å and the steric limitations are defined by van der Waals difference mapping.
- 99Rajapakse, H. A.; Nantermet, P. G.; Selnick, H. G.; Munshi, S.; McGaughey, G. B.; Lindsley, S. R.; Young, M. B.; Lai, M. T.; Espeseth, A. S.; Shi, X. P.; Colussi, D.; Pietrak, B.; Crouthamel, M. C.; Tugusheva, K.; Huang, Q.; Xu, M.; Simon, A. J.; Kuo, L.; Hazuda, D. J.; Graham, S.; Vacca, J. P. Discovery of oxadiazoyl tertiary carbinamine inhibitors of β-secretase (BACE-1). J. Med. Chem. 2006, 49, 7270– 7273, DOI: 10.1021/jm061046r[ACS Full Text], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtF2it7fE&md5=ff27839eaa2f89f85fb53a19d3cb32bcDiscovery of Oxadiazoyl Tertiary Carbinamine Inhibitors of β-Secretase (BACE-1)Rajapakse, Hemaka A.; Nantermet, Philippe G.; Selnick, Harold G.; Munshi, Sanjeev; McGaughey, Georgia B.; Lindsley, Stacey R.; Young, Mary Beth; Lai, Ming-Tain; Espeseth, Amy S.; Shi, Xiao-Ping; Colussi, Dennis; Pietrak, Beth; Crouthamel, Ming-Chih; Tugusheva, Katherine; Huang, Qian; Xu, Min; Simon, Adam J.; Kuo, Lawrence; Hazuda, Daria J.; Graham, Samuel; Vacca, Joseph P.Journal of Medicinal Chemistry (2006), 49 (25), 7270-7273CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme β-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.
- 100Pitasse-Santos, P.; Sueth-Santiago, V.; Lima, M. E. F. 1,2,4- and 1,3,4-Oxadiazoles as scaffolds in the development of antiparasitic agents. J. Braz. Chem. Soc. 2018, 29, 435– 456, DOI: 10.21577/0103-5053.20170208[Crossref], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXps1Oqug%253D%253D&md5=21cbe0ccdb4af49b9042c57752afbfa01,2,4- and 1,3,4-oxadiazoles as scaffolds in the development of antiparasitic agentsPitasse-Santos, Paulo; Sueth-Santiago, Vitor; Lima, Marco E. F.Journal of the Brazilian Chemical Society (2018), 29 (3), 435-456CODEN: JOCSET; ISSN:1678-4790. (Sociedade Brasileira de Quimica)In this review, we present the potential use of the heterocyclic oxadiazole rings in the design and synthesis of new drugs to treat parasitic infections. We intend to compare herein all the four isomeric forms of oxadiazole rings as well as discuss the differences and similarities between them. In addn., we discuss aspects on their reactivity that justify the great importance of both 1,2,4- and 1,3,4-oxadiazoles isomers when compared with their other two isomers. Although some oxadiazole isomers satisfy H.ovrddot.uckel's rule, there are differences concerning their aromaticity, which have a great impact on the possible interactions of the oxadiazole ring with biol. receptors. The set of works selected from the literature and discussed herein points out the oxadiazole core as an important and versatile scaffold in the development of new chem. entities potentially useful as antiparasitic drugs.
- 101Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.; Terenius, L.; Luthman, K. Design, synthesis, and evaluation of phe-gly mimetics: heterocyclic building blocks for pseudopeptides. J. Med. Chem. 1999, 42, 4331– 4342, DOI: 10.1021/jm990197+[ACS Full Text], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmt12ltr4%253D&md5=2aa8bee89cec206a816462cfd2d5729bDesign, Synthesis, and Evaluation of Phe-Gly Mimetics: Heterocyclic Building Blocks for PseudopeptidesBorg, Susanna; Vollinga, Roeland C.; Labarre, Maryse; Payza, Kemal; Terenius, Lars; Luthman, KristinaJournal of Medicinal Chemistry (1999), 42 (21), 4331-4342CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Enantiopure heterocyclic Boc-protected Phe-Gly dipeptidomimetics contg. 1,3,4-oxadiazole, 1,2,4-oxadiazole, and 1,2,4-triazole ring systems have been synthesized as building blocks in the synthesis of pseudopeptides. Three derivs. have the carboxylic acid function directly bound to the heterocyclic ring, and three derivs. have an extra methylene group between the heterocyclic ring and the acid function to allow for an increased conformational flexibility. The mimetics were used as Phe-Gly replacements in the biol. active peptides dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) and substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-MetNH2, SP). The pseudopeptide synthesis was performed using solid-phase methodol. on a MBHA-resin using Boc-chem. The biol. evaluation was performed by testing the μ- and δ-opioid receptor affinities of the dermorphin pseudopeptides and the NK1 receptor affinities of the SP pseudopeptides. The results showed that all mimetics except 1,2,4-triazole were excellent replacements of Phe-Gly in dermorphin since they displayed affinities for the μ-receptor (IC50 = 12-31 nM) in the same range as dermorphin itself (IC50 = 6.2 nM). The agonist activity of three pseudopeptides at human μ-receptors was also evaluated. It was shown that the tested compds. retained their agonist activity. The SP pseudopeptides showed considerably lower affinities (IC50 > 1 μM) for the NK1 receptor than SP itself (IC50 = 1.5 nM) indicating that the Phe-Gly replacements prevent the pseudopeptides from adopting bioactive conformations.
- 102Wolfe, M. S. γ-Secretase inhibitors and modulators for Alzheimer’s disease. J. Neurochem. 2012, 120 (Suppl. 1), 89– 98, DOI: 10.1111/j.1471-4159.2011.07501.x[Crossref], [PubMed], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFyns70%253D&md5=f495ec06da422076c7110ea4d0d37bbbγ-secretase inhibitors and modulators for Alzheimer's diseaseWolfe, Michael S.Journal of Neurochemistry (2012), 120 (Suppl. 1), 89-98CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)A review. γ-Secretase is a membrane embedded aspartyl protease complex with presenilin as the catalytic component. Along with β-secretase, this enzyme produces the amyloid β-protein of Alzheimer's disease (AD) from the amyloid β-protein precursor. Because of its key role in the pathogenesis of AD, γ-secretase has been a prime target for drug discovery, and many inhibitors of this protease have been developed. The therapeutic potential of these inhibitors is virtually negated by the fact that γ-secretase is an essential part of the Notch signaling pathway, rendering the compds. unacceptably toxic upon chronic exposure. However, these compds. have served as useful chem. tools for biol. investigations. In contrast, γ-secretase modulators continue to be of keen interest as possible AD therapeutics. These modulators either shift amyloid β-protein prodn. to shorter, less pathogenic peptides or inhibit the proteolysis of amyloid β-protein precursor selectively compared to that of Notch. The various chem. types of inhibitors and modulators will be discussed, along with their use as probes for basic biol. and their potential as AD therapeutics.
- 103Wolfe, M. S. Unlocking truths of γ-secretase in Alzheimer’s disease: what is the translational potential?. Future Neurol. 2014, 9, 419– 429, DOI: 10.2217/fnl.14.35[Crossref], [PubMed], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFymtb7I&md5=4326261d5bcfe4c7d22b1cadd160a650Unlocking truths of γ-secretase in Alzheimer's disease: what is the translational potential?Wolfe, Michael S.Future Neurology (2014), 9 (4), 419-429CODEN: FNUEAM; ISSN:1479-6708. (Future Medicine Ltd.)Considerable evidence, particularly from genetics, points to the aggregation-prone amyloid β-peptide as a pathogenic entity in Alzheimer's disease. Hence, the proteases that produce this peptide from its precursor protein have been prime targets for the development of potential therapeutics. One of these proteases, γ-secretase, has been a particular focus. Many inhibitors and modulators of this membrane-embedded protease complex have been identified, with some brought into late-stage clin. trials, where they have spectacularly failed. The reasons for these failures will be discussed, along with recent findings on the mechanism of γ-secretase and of Alzheimer-causing mutations that may suggest new strategies for targeting this enzyme.
- 104D’Onofrio, G.; Panza, F.; Frisardi, V.; Solfrizzi, V.; Imbimbo, B. P.; Paroni, G.; Cascavilla, L.; Seripa, D.; Pilotto, A. Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer’s disease. Expert Opin. Drug Discovery 2012, 7, 19– 37, DOI: 10.1517/17460441.2012.645534[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1Wjsg%253D%253D&md5=7bb55128f95a0e5d0aa28465cb9e0441Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer's diseaseD'Onofrio, Grazia; Panza, Francesco; Frisardi, Vincenza; Solfrizzi, Vincenzo; Imbimbo, Bruno P.; Paroni, Giulia; Cascavilla, Leandro; Seripa, Davide; Pilotto, AlbertoExpert Opinion on Drug Discovery (2012), 7 (1), 19-37CODEN: EODDBX; ISSN:1746-0441. (Informa Healthcare)A review. Introduction: In an attempt of altering the natural history of Alzheimer's disease (AD), several compds. have been developed with the aim of inhibiting γ-secretase, the enzymic complex generating β-amyloid (Aβ) peptides (Aβ1 - 40 and Aβ1 - 42), from amyloid precursor protein (APP). APP is believed to be involved in the pathophysiol. cascade of AD.Areas covered: This article briefly reviews the profile of γ-secretase inhibitors that have reached the clinic. The paper reviews studies from the primary English literature on γ-secretase inhibitors published before Nov. 2011, searching through the PubMed database of NCBI by author and the following keywords: drugs targeting β-amyloid, γ-secretase inhibitors, dementia syndromes and Alzheimer's disease.Expert opinion: Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concns. However, scanty data are available on the effects of these compds. on brain Aβ deposition after prolonged administration. γ-Secretase inhibitors may cause significant toxicity in exptl. animals and in humans believed to be assocd. with the inhibition of the cleavage of Notch, a transmembrane receptor involved in regulating cell-fate decisions. Unfortunately, two large Phase III clin. trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effects of the drug, possibly due to its lack of selectivity on APP processing. New APP-selective γ-secretase inhibitors are being developed with the hope of overcoming the previous setbacks.
- 105Gillman, K. W.; Starrett, J. E., Jr.; Parker, M. F.; Xie, K.; Bronson, J. J.; Marcin, L. R.; McElhone, K. E.; Bergstrom, C. P.; Mate, R. A.; Williams, R.; Meredith, J. E., Jr.; Burton, C. R.; Barten, D. M.; Toyn, J. H.; Roberts, S. B.; Lentz, K. A.; Houston, J. G.; Zaczek, R.; Albright, C. F.; Decicco, C. P.; Macor, J. E.; Olson, R. E. Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable γ-secretase inhibitor. ACS Med. Chem. Lett. 2010, 1, 120– 124, DOI: 10.1021/ml1000239[ACS Full Text], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjs1WrsL0%253D&md5=f28ebc4be6022fdbe9297c8663588440Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase InhibitorGillman, Kevin W.; Starrett, John E.; Parker, Michael F.; Xie, Kai; Bronson, Joanne J.; Marcin, Lawrence R.; McElhone, Kate E.; Bergstrom, Carl P.; Mate, Robert A.; Williams, Richard; Meredith, Jere E.; Burton, Catherine R.; Barten, Donna M.; Toyn, Jeremy H.; Roberts, Susan B.; Lentz, Kimberley A.; Houston, John G.; Zaczek, Robert; Albright, Charles F.; Decicco, Carl P.; Macor, John E.; Olson, Richard E.ACS Medicinal Chemistry Letters (2010), 1 (3), 120-124CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-β precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compd. 4 is a potent inhibitor of γ-secretase (Aβ40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.
- 106Koufaki, M.; Theodorou, E.; Alexi, X.; Alexis, M. N. Synthesis of a second generation chroman/catechol hybrids and evaluation of their activity in protecting neuronal cells from oxidative stress-induced cell death. Bioorg. Med. Chem. 2010, 18, 3898– 3909, DOI: 10.1016/j.bmc.2010.04.042[Crossref], [PubMed], [CAS], Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmslOis7w%253D&md5=31692e88f11ad931193fad1b42c132b9Synthesis of a second generation chroman/catechol hybrids and evaluation of their activity in protecting neuronal cells from oxidative stress-induced cell deathKoufaki, Maria; Theodorou, Elissavet; Alexi, Xanthippi; Alexis, Michael N.Bioorganic & Medicinal Chemistry (2010), 18 (11), 3898-3909CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)A new generation of chroman/catechol hybrids bearing heterocyclic five-membered rings, such as 1,2,4-oxadiazole 1,3,4-oxadiazole, 1,2,3-triazole, tetrazole and isoxazole, were designed and synthesized. The activity of the new derivs. against oxidative stress induced neuronal damage, was evaluated using glutamate-challenged hippocampal HT22 cells. Compd. 3 in which a 3,4-dimethoxyphenyl moiety, is directly attached to the 1,2,4-oxadiazole ring was the most active among the 2-substituted chroman analogs, with EC50 = 254 ± 65 nM. Concerning the 5-substituted chroman analogs, isoxazole deriv. 29 exhibited the strongest activity (EC50 = 245 ± 38 nM). However, 29 was cytotoxic at concns. higher than 1 μM, while the triazole analog 24 (EC50 = 801 ± 229 nM), was non-toxic at all concns. tested.
- 107Reed, C. W.; Washecheck, J. P.; Quitlag, M. C.; Jenkins, M. T.; Rodriguez, A. L.; Engers, D. W.; Blobaum, A. L.; Jeffrey Conn, P.; Niswender, C. M.; Lindsley, C. W. Surveying heterocycles as amide bioisosteres within a series of mGlu7 NAMs: discovery of VU6019278. Bioorg. Med. Chem. Lett. 2019, 29, 1211– 1214, DOI: 10.1016/j.bmcl.2019.03.016[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmtVCntLg%253D&md5=6d4390eab59aec1506829378170fd4ffSurveying heterocycles as amide bioisosteres within a series of mGlu7 NAMs: Discovery of VU6019278Reed, Carson W.; Washecheck, Jordan P.; Quitlag, Marc C.; Jenkins, Matthew T.; Rodriguez, Alice L.; Engers, Darren W.; Blobaum, Anna L.; Jeffrey Conn, P.; Niswender, Colleen M.; Lindsley, Craig W.Bioorganic & Medicinal Chemistry Letters (2019), 29 (10), 1211-1214CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)This letter describes a diversity-oriented library approach to rapidly assess diverse heterocycles as bioisosteric replacements for a metabolically labile amide moiety within a series of mGlu7 neg. allosteric modulators (NAMs). SAR rapidly honed in on either a 1,2,4- or 1,3,4-oxadizaole ring system as an effective bioisostere for the amide. Further optimization of the southern region of the mGlu7 NAM chemotype led to the discovery of VU6019278, a potent mGlu7 NAM (IC50 = 501 nM, 6.3% L-AP4 Min) with favorable plasma protein binding (rat fu = 0.10), low predicted hepatic clearance (rat CLhep = 27.7 mL/min/kg) and high CNS penetration (rat Kp = 4.9, Kp,uu = 0.65).
- 108Reed, C. W.; McGowan, K. M.; Spearing, P. K.; Stansley, B. J.; Roenfanz, H. F.; Engers, D. W.; Rodriguez, A. L.; Engelberg, E. M.; Luscombe, V. B.; Loch, M. T.; Remke, D. H.; Rook, J. M.; Blobaum, A. L.; Conn, P. J.; Niswender, C. M.; Lindsley, C. W. VU6010608, a novel mGlu7 NAM from a series of N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamides. ACS Med. Chem. Lett. 2017, 8, 1326– 1330, DOI: 10.1021/acsmedchemlett.7b00429[ACS Full Text], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslyrsLzN&md5=56d5c5d5a07a3c823de9be5ee44764c7VU6010608, a Novel mGlu7 NAM from a Series of N-(2-(1H-1,2,4-Triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamidesReed, Carson W.; McGowan, Kevin M.; Spearing, Paul K.; Stansley, Branden J.; Roenfanz, Hanna F.; Engers, Darren W.; Rodriguez, Alice L.; Engelberg, Eileen M.; Luscombe, Vincent B.; Loch, Matthew T.; Remke, Daniel H.; Rook, Jerri M.; Blobaum, Anna L.; Conn, P. Jeffrey; Niswender, Colleen M.; Lindsley, Craig W.ACS Medicinal Chemistry Letters (2017), 8 (12), 1326-1330CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Herein, we report the structure-activity relationships within a series of mGlu7 NAMs based on an N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamide core with excellent CNS penetration (Kp 1.9-5.8 and Kp,uu 0.4-1.4). Analogs in this series displayed steep SAR. Of these, VU6010608 (11a) emerged with robust efficacy in blocking high frequency stimulated long-term potentiation in electrophysiol. studies.
- 109Reed, C. W.; Yohn, S. E.; Washecheck, J. P.; Roenfanz, H. F.; Quitalig, M. C.; Luscombe, V. B.; Jenkins, M. T.; Rodriguez, A. L.; Engers, D. W.; Blobaum, A. L.; Conn, P. J.; Niswender, C. M.; Lindsley, C. W. Discovery of an orally bioavailable and central nervous system (CNS) penetrant mGlu7 negative allosteric modulator (NAM) in vivo tool compound: N-(2-(1 H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962). J. Med. Chem. 2019, 62, 1690– 1695, DOI: 10.1021/acs.jmedchem.8b01810[ACS Full Text], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslCrtA%253D%253D&md5=812a024a3b5708bab2111dfce104fd2eDiscovery of an orally bioavailable and central nervous system (CNS) penetrant mGlu7 negative allosteric modulator (NAM) in vivo tool compound: N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962)Reed, Carson W.; Yohn, Samantha E.; Washecheck, Jordan P.; Roenfanz, Hanna F.; Quitalig, Marc C.; Luscombe, Vincent B.; Jenkins, Matthew T.; Rodriguez, Alice L.; Engers, Darren W.; Blobaum, Anna L.; Conn, P. Jeffrey; Niswender, Colleen M.; Lindsley, Craig W.Journal of Medicinal Chemistry (2019), 62 (3), 1690-1695CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Herein, we report the discovery of a new, orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu7) neg. allosteric modulator I that achieves exposure in cerebral spinal fluid (CSF) 2.5× above the in vitro IC50 at min. EDs (MEDs) of 3 mg/kg in preclin. anxiety models.
- 110Nordhoff, S.; Bulat, S.; Cerezo-Galvez, S.; Hill, O.; Hoffmann-Enger, B.; Lopez-Canet, M.; Rosenbaum, C.; Rummey, C.; Thiemann, M.; Matassa, V. G.; Edwards, P. J.; Feurer, A. The design of potent and selective inhibitors of DPP-4: optimization of ADME properties by amide replacements. Bioorg. Med. Chem. Lett. 2009, 19, 6340– 6345, DOI: 10.1016/j.bmcl.2009.09.078[Crossref], [PubMed], [CAS], Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlWlsrfK&md5=04692309b3fa450f5799446702ecd089The design of potent and selective inhibitors of DPP-4: Optimization of ADME properties by amide replacementsNordhoff, Sonja; Bulat, Stephan; Cerezo-Galvez, Silvia; Hill, Oliver; Hoffmann-Enger, Barbara; Lopez-Canet, Meritxell; Rosenbaum, Claudia; Rummey, Christian; Thiemann, Meinolf; Matassa, Victor G.; Edwards, Paul J.; Feurer, AchimBioorganic & Medicinal Chemistry Letters (2009), 19 (22), 6340-6345CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)For a series of β-homophenylalanine based inhibitors of dipeptidyl peptidase IV, ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.
- 111Makrilakis, K. The role of DPP-4 inhibitors in the treatment algorithm of type 2 diabetes mellitus: when to select, what to expect. Int. J. Environ. Res. Public Health 2019, 16, 2720, DOI: 10.3390/ijerph16152720[Crossref], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVGmt7vL&md5=246f6f9640899f76ddf54b1abfe0b1c2The role of DPP-4 inhibitors in the treatment algorithm of type 2 diabetes mellitus: when to select, what to expectMakrilakis, KonstantinosInternational Journal of Environmental Research and Public Health (2019), 16 (15), 2720CODEN: IJERGQ; ISSN:1660-4601. (MDPI AG)A review. Type 2 diabetes mellitus is a growing global public health problem, the prevalence of which is projected to increase in the succeeding decades. It is potentially assocd. with many complications, affecting multiple organs and causing a huge burden to the society. Due to its multi-factorial pathophysiol., its treatment is varied and based upon a multitude of pharmacol. agents aiming to tackle the many aspects of the disease pathophysiol. (increasing insulin availability [either through direct insulin administration or through agents that promote insulin secretion], improving sensitivity to insulin, delaying the delivery and absorption of carbohydrates from the gastrointestinal tract, or increasing urinary glucose excretion). DPP-4 (dipeptidyl peptidase-4) inhibitors (or "gliptins") represent a class of oral anti-hyperglycemic agents that inhibit the enzyme DPP-4, thus augmenting the biol. activity of the "incretin" hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) and restoring many of the pathophysiol. problems of diabetes. They have already been used over more than a decade in the treatment of the disease. The current manuscript will review the mechanism of action, therapeutic utility, and the role of DPP-4 inhibitors for the treatment of type 2 diabetes mellitus.
- 112Cao, J.; Zhou, Y.; Peng, H.; Huang, X.; Stahler, S.; Suri, V.; Qadri, A.; Gareski, T.; Jones, J.; Hahm, S.; Perreault, M.; McKew, J.; Shi, M.; Xu, X.; Tobin, J. F.; Gimeno, R. E. Targeting Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases. J. Biol. Chem. 2011, 286, 41838– 41851, DOI: 10.1074/jbc.M111.245456[Crossref], [PubMed], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFaitLbP&md5=fa659203d6b500b82e1a093df2cb40deTargeting Acyl-CoA:Diacylglycerol Acyltransferase 1 (DGAT1) with Small Molecule Inhibitors for the Treatment of Metabolic DiseasesCao, Jingsong; Zhou, Yingjiang; Peng, Haibing; Huang, Xinyi; Stahler, Shannon; Suri, Vipin; Qadri, Ariful; Gareski, Tiffany; Jones, Juli; Hahm, Seung; Perreault, Mylene; McKew, John; Shi, Mengxiao; Xu, Xin; Tobin, James F.; Gimeno, Ruth E.Journal of Biological Chemistry (2011), 286 (48), 41838-41851, S41838/1-S41838/3CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in triglyceride synthesis. Findings from genetically modified mice as well as pharmacol. studies suggest that inhibition of DGAT1 is a promising strategy for the treatment of obesity and type 2 diabetes. Here we characterize a tool DGAT1 inhibitor compd., T863. We found that T863 is a potent inhibitor for both human and mouse DGAT1 in vitro, which acts on the acyl-CoA binding site of DGAT1 and inhibits DGAT1-mediated triacylglycerol formation in cells. In an acute lipid challenge model, oral administration of T863 significantly delayed fat absorption and resulted in lipid accumulation in the distal small intestine of mice, mimicking the effects of genetic ablation of DGAT1. In diet-induced obese mice, oral administration of T863 for 2 wk caused wt. loss, redn. in serum and liver triglycerides, and improved insulin sensitivity. In addn. to the expected triglyceride-lowering activity, T863 also lowered serum cholesterol. Hepatic IRS2 protein was dramatically up-regulated in mice treated with T863, possibly contributing to improved insulin sensitivity. In differentiated 3T3-L1 adipocytes, T863 enhanced insulin-stimulated glucose uptake, suggesting a possible role for adipocytes to improve insulin sensitivity upon DGAT1 inhibition. These results reveal novel mechanistic insights into the insulin-sensitizing effects of DGAT1 inhibition in mouse models. Taken together, our study provides a comprehensive evaluation of a small mol. inhibitor for DGAT1 and suggests that pharmacol. inhibition of DGAT1 holds promise in treating diverse metabolic disorders.
- 113Nakajima, K.; Chatelain, R.; Clairmont, K. B.; Commerford, R.; Coppola, G. M.; Daniels, T.; Forster, C. J.; Gilmore, T. A.; Gong, Y.; Jain, M.; Kanter, A.; Kwak, Y.; Li, J.; Meyers, C. D.; Neubert, A. D.; Szklennik, P.; Tedesco, V.; Thompson, J.; Truong, D.; Yang, Q.; Hubbard, B. K.; Serrano-Wu, M. H. Discovery of an orally bioavailable benzimidazole diacylglycerol acyltransferase 1 (DGAT1) inhibitor that suppresses body weight gain in diet-induced obese dogs and postprandial triglycerides in humans. J. Med. Chem. 2017, 60, 4657– 4664, DOI: 10.1021/acs.jmedchem.7b00173[ACS Full Text], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXns1Wmt7Y%253D&md5=2583c74a8cf9478075df49cacc72864bDiscovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in HumansNakajima, Katsumasa; Chatelain, Ricardo; Clairmont, Kevin B.; Commerford, Renee; Coppola, Gary M.; Daniels, Thomas; Forster, Cornelia J.; Gilmore, Thomas A.; Gong, Yongjin; Jain, Monish; Kanter, Aaron; Kwak, Youngshin; Li, Jingzhou; Meyers, Charles D.; Neubert, Alan D.; Szklennik, Paul; Tedesco, Vivienne; Thompson, James; Truong, David; Yang, Qing; Hubbard, Brian K.; Serrano-Wu, Michael H.Journal of Medicinal Chemistry (2017), 60 (11), 4657-4664CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Modification of a gut restricted class of benzimidazole DGAT1 inhibitor I led to II with good oral bioavailability. The key structural changes to I include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both I and II can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only II was found to be effective in suppressing body wt. gain relative to control in a diet induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body wt. control. II has advanced to clin. investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans.
- 114Serrano-Wu, M. H.; Coppola, G. M.; Gong, Y.; Neubert, A. D.; Chatelain, R.; Clairmont, K. B.; Commerford, R.; Cosker, T.; Daniels, T.; Hou, Y.; Jain, M.; Juedes, M.; Li, L.; Mullarkey, T.; Rocheford, E.; Sung, M. J.; Tyler, A.; Yang, Q.; Yoon, T.; Hubbard, B. K. Intestinally targeted diacylglycerol acyltransferase 1 (DGAT1) inhibitors robustly suppress postprandial triglycerides. ACS Med. Chem. Lett. 2012, 3, 411– 415, DOI: 10.1021/ml3000512[ACS Full Text], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkvFWktLk%253D&md5=4296446fcf69fdf96acf38156c84b950Intestinally Targeted Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors Robustly Suppress Postprandial TriglyceridesSerrano-Wu, Michael H.; Coppola, Gary M.; Gong, Yongjin; Neubert, Alan D.; Chatelain, Ricardo; Clairmont, Kevin B.; Commerford, Renee; Cosker, Theresa; Daniels, Thomas; Hou, Ying; Jain, Monish; Juedes, Marlene; Li, Lisha; Mullarkey, Tara; Rocheford, Erik; Sung, Moo Je; Tyler, Andrew; Yang, Qing; Yoon, Taeyoung; Hubbard, Brian K.ACS Medicinal Chemistry Letters (2012), 3 (5), 411-415CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)High DGAT1 expression levels in the small intestine highlight the crit. role this enzyme plays in nutrient absorption. Identification of inhibitors which predominantly inhibit DGAT1 in the gut is an attractive drug discovery strategy with anticipated benefits of reduced systemic toxicity. In this report we describe our discovery and optimization of DGAT1 inhibitors whose plasma exposure is minimized by the action of transporters, including the P-glycoprotein transporter. The impact of this unique absorption profile on efficacy in rat and dog efficacy models is presented.
- 115Pasquini, S.; Ligresti, A.; Mugnaini, C.; Semeraro, T.; Cicione, L.; De Rosa, M.; Guida, F.; Luongo, L.; De Chiaro, M.; Cascio, M. G.; Bolognini, D.; Marini, P.; Pertwee, R.; Maione, S.; Di Marzo, V.; Corelli, F. Investigations on the 4-quinolone-3-carboxylic acid motif. 3. synthesis, structure-affinity relationships, and pharmacological characterization of 6-substituted 4-quinolone-3-carboxamides as highly selective cannabinoid-2 receptor ligands. J. Med. Chem. 2010, 53, 5915– 5928, DOI: 10.1021/jm100123x[ACS Full Text], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpsVCht78%253D&md5=642a103b93312fd2f1e124173143b656Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 3. Synthesis, Structure-Affinity Relationships, and Pharmacological Characterization of 6-Substituted 4-Quinolone-3-carboxamides as Highly Selective Cannabinoid-2 Receptor LigandsPasquini, Serena; Ligresti, Alessia; Mugnaini, Claudia; Semeraro, Teresa; Cicione, Lavinia; De Rosa, Maria; Guida, Francesca; Luongo, Livio; De Chiaro, Maria; Cascio, Maria Grazia; Bolognini, Daniele; Marini, Pietro; Pertwee, Roger; Maione, Sabatino; Di Marzo, Vincenzo; Corelli, FedericoJournal of Medicinal Chemistry (2010), 53 (16), 5915-5928CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A set of quinolone-3-carboxamides I [R1 = (un)substituted Ph, 2-furyl, 1-cyclohexenyl, 1-isobutylpyrazol-4-yl, etc.; R2 = 1-adamantyl, 1-fenchyl, hexyl, 1-piperidinyl; R3 = pentyl, 1-buten-4-yl, allyl] bearing diverse substituents at position 1, 3, and 6 of the bicyclic nucleus was prepd. Except for six compds. exhibiting Ki > 100 nM, all the quinolone-3-carboxamides I proved to be high affinity CB2 ligands, with Ki values ranging from 73.2 to 0.7 nM and selectivity [SI = Ki(CB1)/Ki(CB2)] varying from >14285 to 1.9, with only one compd. exhibiting a reverse selectivity (SI < 1). In the formalin test of peripheral acute and inflammatory pain in mice, I [R1 = CH2CH2Ph, R2 = 1-adamantyl, R3 = pentyl] showed analgesic activity that was antagonized by a selective CB2 antagonist. By contrast, I [R1 = 2-furyl, R2 = 1-adamantyl, R3 = pentyl] was inactive per se and antagonized the effect of a selective CB2 agonist. Also, two of these compds. exhibited CB2 inverse agonist-like behavior in this in vivo test. However, two different functional assays carried out in vitro indicated for both compds. an overall inverse agonist activity at CB2 receptors.
- 116Pasquini, S.; Botta, L.; Semeraro, T.; Mugnaini, C.; Ligresti, A.; Palazzo, E.; Maione, S.; Di Marzo, V.; Corelli, F. Investigations on the 4-quinolone-3-carboxylic acid motif. 2. synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivo. J. Med. Chem. 2008, 51, 5075– 5084, DOI: 10.1021/jm800552f[ACS Full Text], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptl2htro%253D&md5=5c461877098aec3a53c31676ced30c98Investigations on the 4-quinolone-3-carboxylic acid motif. 2. synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivoPasquini, Serena; Botta, Lorenzo; Semeraro, Teresa; Mugnaini, Claudia; Ligresti, Alessia; Palazzo, Enza; Maione, Sabatino; Di Marzo, Vincenzo; Corelli, FedericoJournal of Medicinal Chemistry (2008), 51 (16), 5075-5084CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Quinolone-3-carboxamides bearing at position 5, 6, 7, or 8 diverse substituents such as halides, alkyl, aryl, alkoxy, and aryloxy groups differing in their steric/electronic properties, were prepd. The new compds. were tested in vitro for CB1 and CB2 receptor affinity in comparison with the ref. compds. rimonabant and SR144528. The tested compds. exhibited CB2 affinity in the range from 55.9 to 0.8 nM and CB1 affinity in the range from >10 000 to 5.3 nM, with selectivity indeces [Ki(CB1)/Ki(CB2)] varying from >2666.6 to 1.23. On the basis of the structure-selectivity relationship developed, the presence of a substituent at C6/C8 or C7 well accounts for the high or low CB2 selectivity, resp. Compd. I, characterized by high CB2 affinity and selectivity, showed analgesic activity in the formalin test of acute peripheral and inflammatory pain in mice as a result of selective CB2 agonistic activity.
- 117Pasquini, S.; De Rosa, M.; Pedani, V.; Mugnaini, C.; Guida, F.; Luongo, L.; De Chiaro, M.; Maione, S.; Dragoni, S.; Frosini, M.; Ligresti, A.; Di Marzo, V.; Corelli, F. Investigations on the 4-quinolone-3-carboxylic acid motif. 4. identification of new potent and selective ligands for the cannabinoid type 2 receptor with diverse substitution patterns and antihyperalgesic effects in mice. J. Med. Chem. 2011, 54, 5444– 5453, DOI: 10.1021/jm200476p[ACS Full Text], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXosFCgtbo%253D&md5=4b9daccdccfddbbde2ef53fcca4a87bdInvestigations on the 4-Quinolone-3-carboxylic Acid Motif. 4. Identification of New Potent and Selective Ligands for the Cannabinoid Type 2 Receptor with Diverse Substitution Patterns and Antihyperalgesic Effects in MicePasquini, Serena; De Rosa, Maria; Pedani, Valentina; Mugnaini, Claudia; Guida, Francesca; Luongo, Livio; De Chiaro, Maria; Maione, Sabatino; Dragoni, Stefania; Frosini, Maria; Ligresti, Alessia; Di Marzo, Vincenzo; Corelli, FedericoJournal of Medicinal Chemistry (2011), 54 (15), 5444-5453CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Exptl. evidence suggests that selective CB2 receptor modulators may provide access to antihyperalgesic agents devoid of psychotropic effects. Taking advantage of previous findings on structure-activity/selectivity relationships for a class of 4-quinolone-3-carboxamides, further structural modifications of the heterocyclic scaffold were explored, leading to the discovery of the 8-methoxy deriv. 4a endowed with the highest affinity and selectivity ever reported for a CB2 ligand. The compd., evaluated in vivo in the formalin test, behaved as an inverse agonist by reducing at a dose of 6 mg/kg the second phase of the formalin-induced nocifensive response in mice.
- 118Dundee, J. W.; Halliday, N. J.; Harper, K. W.; Brogden, R. N. Midazolam. a review of its pharmacological properties and therapeutic use. Drugs 1984, 28, 519– 543, DOI: 10.2165/00003495-198428060-00002[Crossref], [PubMed], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXlsFCrtA%253D%253D&md5=50690cc356b140a8c337a883f26d07d5Midazolam. A review of its pharmacological properties and therapeutic useDundee, J. W.; Halliday, N. J.; Harper, K. W.; Brogden, R. N.Drugs (1984), 28 (6), 519-43CODEN: DRUGAY; ISSN:0012-6667.A review with ∼194 refs. on the pharmacodynamics, pharmacokinetics, and therapeutic use of midazolam [59467-70-8].
- 119Gerecke, M. Chemical structure and properties of midazolam compared with other benzodiazepines. Br. J. Clin. Pharmacol. 1983, 16 (Suppl. 1), 11S– 16S, DOI: 10.1111/j.1365-2125.1983.tb02266.x[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXlsFWmt7g%253D&md5=0cee5dcfe1e1dfbe14d189c3b1426ba8Chemical structure and properties of midazolam compared with other benzodiazepinesGerecke, M.British Journal of Clinical Pharmacology (1983), 16 (Suppl. 1), 11-16CODEN: BCPHBM; ISSN:0306-5251.A short review is with 31 refs. on the basic chem. development in the field of "classical" and "annelated" benzodiazepines, distinguishing between pro-drugs and directly acting compds. Some properties of midazolam (I) [59467-70-8] that are of special interest for its practical use are discussed.
- 120Taghizadeh, M. J.; Malakpouri, G. r.; Javidan, A. Improved and scalable methods for the synthesis of midazolam drug and its analogues using isocyanide reagents. J. Iran. Chem. Soc. 2019, 16, 785– 794, DOI: 10.1007/s13738-018-1555-0[Crossref], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFOnur%252FM&md5=c1b88291efb948a2dfc08a8ae558af27Improved and scalable methods for the synthesis of midazolam drug and its analogues using isocyanide reagentsTaghizadeh, Mohammad Javad; malakpouri, Gholam reza; Javidan, AbdollahJournal of the Iranian Chemical Society (2019), 16 (4), 785-794CODEN: JICSCJ; ISSN:1735-207X. (Springer GmbH)Two improved and scalable methods for the synthesis of midazolam and its analogs was described. Midazolam was synthesized using isocyanide reagents in satisfactory yield. In this methodol., imidazobenzodiazepine intermediates were easily prepd. via an improved process. One-pot condensation of benzodiazepines with mono-anion of tosylmethyl isocyanide or Et isocyanoacetate under mild condition led to formation of imidazobenzodiazepine. In the first method, tosylmethyl isocyanide (Tos-MIC) was used and the no. of synthetic steps were decreased in comparison to previous report. In the second method, Et isocyanoacetate which was commonly used for the synthesis of some imidazobenzodiazepines, was consumed to generate midazolam. The latter, a relatively different method for the synthesis of midazolam analogs was reported.
- 121Smith, R.; Brown, J. Midazolam for status epilepticus. Aust. Prescr. 2017, 40, 23– 25, DOI: 10.18773/austprescr.2017.005[Crossref], [PubMed], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czhsFShuw%253D%253D&md5=e97c2ef3121084c1b700fa5fb8455a5fMidazolam for status epilepticusSmith Rob; Brown JanisAustralian prescriber (2017), 40 (1), 23-25 ISSN:0312-8008.There is no expanded citation for this reference.
- 122Vogel, G. W.; Vogel, F. Effect of midazolam on sleep of insomniacs. Br. J. Clin. Pharmacol. 1983, 16 (Suppl. 1), 103S– 108S, DOI: 10.1111/j.1365-2125.1983.tb02279.x
- 123Khanderia, U.; Pandit, S. K. Use of midazolam hydrochloride in anesthesia. Clin. Pharm. 1987, 6, 533– 547[PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1c%252FotFertQ%253D%253D&md5=01e2efd4533e6e595b8848ff225cdc88Use of midazolam hydrochloride in anesthesiaKhanderia U; Pandit S KClinical pharmacy (1987), 6 (7), 533-47 ISSN:0278-2677.The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, dosage, and cost and availability of midazolam hydrochloride are reviewed. The anxiolytic, sedative, hypnotic, anticonvulsant, muscle-relaxant, and amnesic properties of midazolam are similar to those of other injectable benzodiazepines. Midazolam is approximately two to four times as potent as diazepam. Midazolam hydrochloride is water soluble (resulting in fewer local adverse reactions after injection), has a rapid onset and short duration of action, and causes relatively mild cardiovascular and respiratory effects. The drug generally is well tolerated. Midazolam is a good premedicant for general or regional anesthesia. Its greatest use will probably be for conscious sedation during surgical or diagnostic procedures performed under local or regional anesthesia. Induction of anesthesia with midazolam alone is somewhat unpredictable; opiate pretreatment makes induction more consistent. Midazolam is a less reliable induction agent than thiopental, but because it produces fewer adverse cardiovascular and respiratory effects than thiopental, midazolam appears to be a safer induction agent for elderly patients or patients with cardiovascular disease. The recommended dose of midazolam for preoperative sedation is 0.07-0.1 mg/kg given by intramuscular injection one hour before surgery. For conscious sedation, 0.1-0.15 mg/kg intravenously in divided doses is usually adequate. Lower doses of midazolam are recommended for elderly or debilitated patients and patients who have severe liver disease. The costs of equipotent doses of midazolam and injectable diazepam are similar. An oral dosage form is under investigation in the United States. Midazolam's pharmacologic and pharmacokinetic profile makes it an attractive alternative to other injectable benzodiazepines used in anesthesia.
- 124Doods, H.; Arndt, K.; Rudolf, K.; Just, S. CGRP antagonists: unravelling the role of CGRP in migraine. Trends Pharmacol. Sci. 2007, 28, 580– 587, DOI: 10.1016/j.tips.2007.10.005[Crossref], [PubMed], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1KgsLrO&md5=c3295a79a4571c61b56215b0b1760b52CGRP antagonists: unravelling the role of CGRP in migraineDoods, Henri; Arndt, Kirsten; Rudolf, Klaus; Just, StefanTrends in Pharmacological Sciences (2007), 28 (11), 580-587CODEN: TPHSDY; ISSN:0165-6147. (Elsevier B.V.)A review. Migraine is a complex, debilitating neurovascular disorder. Although knowledge on the main mol. players is still incomplete, recent preclin. and clin. findings indicate that there is a clear correlation between migraine-assocd. headache and the release of the neuropeptide calcitonin gene-related peptide (CGRP). BIBN4096 was the first CGRP antagonist to be tested in clin. trials for the treatment of migraine. The proven efficacy of this agent, and also the CGRP antagonist MK-0974, to alleviate acute migraine headache provided significant support for the hypothesis that CGRP has an important role in migraine pathophysiol. Moreover, the recently published results from Phase II trials are encouraging and suggest that this new type of drug might offer advantages over existing therapies for patients suffering from migraine and related headaches.
- 125Bell, I. M. Calcitonin gene-related peptide receptor antagonists: new therapeutic agents for migraine. J. Med. Chem. 2014, 57, 7838– 7858, DOI: 10.1021/jm500364u[ACS Full Text], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVentb7O&md5=ef228d3b829dd642d50eb00e6868ac82Calcitonin Gene-Related Peptide Receptor Antagonists: New Therapeutic Agents for MigraineBell, Ian M.Journal of Medicinal Chemistry (2014), 57 (19), 7838-7858CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Calcitonin gene-related peptide (CGRP) is a potent neuromodulator and vasodilator. It has been implicated in the pathogenesis of migraine by a no. of lines of evidence, although its precise role has yet to be fully defined. Compelling evidence for the importance of CGRP in migraine has been provided by clin. trials with multiple small mol. CGRP receptor antagonists. These clin. studies have shown that blockade of the CGRP receptor can produce antimigraine efficacy comparable to that of the gold std. triptan class of drugs with an incidence of adverse events that appears to be relatively low. The present review describes the discovery and development of these new antimigraine agents and highlights the challenges of identifying orally acting drugs that target a family B G-protein-coupled receptor.
- 126Deen, M.; Correnti, E.; Kamm, K.; Kelderman, T.; Papetti, L.; Rubio-Beltran, E.; Vigneri, S.; Edvinsson, L.; Maassen Van Den Brink, A. Blocking CGRP in migraine patients - a review of pros and cons. J. Headache Pain 2017, 18, 96, DOI: 10.1186/s10194-017-0807-1[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M%252FitlKitA%253D%253D&md5=e78ce644d8a98e89ab1a73a62b16b79dBlocking CGRP in migraine patients - a review of pros and consDeen Marie; Correnti Edvige; Kamm Katharina; Kelderman Tim; Papetti Laura; Rubio-Beltran Eloisa; Maassen Van Den Brink Antoinette; Vigneri Simone; Edvinsson LarsThe journal of headache and pain (2017), 18 (1), 96 ISSN:.Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs. In general, a superior efficacy compared to placebo has been shown, especially with regards to the antibodies. In addition, the efficacy is in line with other currently used prophylactic treatments. The drugs have also been well tolerated, except for some of the gepants, which induced a transient increase in transaminases. Thus, blocking CGRP in migraine patients is seemingly both efficient and well tolerated. However, CGRP and its receptor are abundantly present in both the vasculature, and in the peripheral and central nervous system, and are involved in several physiological processes. Therefore, blocking CGRP may pose a risk in subjects with comorbidities such as cardiovascular diseases. In addition, long-term effects are still unknown. Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones or attenuate wound healing. However, these effects have so far not been reported in human studies. In conclusion, this review suggests that, based on current knowledge, the pros of blocking CGRP in migraine patients exceeds the cons.
- 127Paone, D. V.; Shaw, A. W.; Nguyen, D. N.; Burgey, C. S.; Deng, J. Z.; Kane, S. A.; Koblan, K. S.; Salvatore, C. A.; Mosser, S. D.; Johnston, V. K.; Wong, B. K.; Miller-Stein, C. M.; Hershey, J. C.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Potent, orally bioavailable calcitonin gene-related peptide receptor antagonists for the treatment of migraine: discovery of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1- (2,2,2-trifluoroethyl)azepan-3-yl]-4- (2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin- 1-yl)piperidine-1-carboxamide (MK-0974). J. Med. Chem. 2007, 50, 5564– 5567, DOI: 10.1021/jm070668p[ACS Full Text], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFCisbfO&md5=cd909611a4a4186e112ad16251be997dPotent, Orally Bioavailable Calcitonin Gene-Related Peptide Receptor Antagonists for the Treatment of Migraine: Discovery of N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1- (2,2,2-trifluoroethyl)azepan-3-yl]-4- (2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin- 1-yl)piperidine-1-carboxamide (MK-0974)Paone, Daniel V.; Shaw, Anthony W.; Nguyen, Diem N.; Burgey, Christopher S.; Deng, James Z.; Kane, Stefanie A.; Koblan, Kenneth S.; Salvatore, Christopher A.; Mosser, Scott D.; Johnston, Victor K.; Wong, Bradley K.; Miller-Stein, Cynthia M.; Hershey, James C.; Graham, Samuel L.; Vacca, Joseph P.; Williams, Theresa M.Journal of Medicinal Chemistry (2007), 50 (23), 5564-5567CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure contg. a (3R)-amino-(6S)-phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivs. with lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group, and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities, ultimately leading to clin. candidate 38 (MK-0974).
- 128Salvatore, C. A.; Hershey, J. C.; Corcoran, H. A.; Fay, J. F.; Johnston, V. K.; Moore, E. L.; Mosser, S. D.; Burgey, C. S.; Paone, D. V.; Shaw, A. W.; Graham, S. L.; Vacca, J. P.; Williams, T. M.; Koblan, K. S.; Kane, S. A. Pharmacological characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. J. Pharmacol. Exp. Ther. 2008, 324, 416– 421, DOI: 10.1124/jpet.107.130344[Crossref], [PubMed], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFShtr4%253D&md5=54a6a42dc952f84881cd6e5aebeba0a5Pharmacological characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraineSalvatore, Christopher A.; Hershey, James C.; Corcoran, Halea A.; Fay, John F.; Johnston, Victor K.; Moore, Eric L.; Mosser, Scott D.; Burgey, Christopher S.; Paone, Daniel V.; Shaw, Anthony W.; Graham, Samuel L.; Vacca, Joseph P.; Williams, Theresa M.; Koblan, Kenneth S.; Kane, Stefanie A.Journal of Pharmacology and Experimental Therapeutics (2008), 324 (2), 416-421CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key role in the pathophysiol. of migraine headache. CGRP levels in the cranial circulation are increased during a migraine attack, and CGRP itself has been shown to trigger migraine-like headache. The correlation between CGRP release and migraine headache points to the potential utility of CGRP receptor antagonists as novel therapeutics in the treatment of migraine. Indeed, clin. proof-of-concept in the acute treatment of migraine was demonstrated with an i.v. formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant). Here we report on the pharmacol. characterization of the first orally bioavailable CGRP receptor antagonist in clin. development, MK-0974. In vitro, MK-0974 is a potent antagonist of the human (Ki = 0.77 nM) and rhesus (Ki = 1.2 nM) CGRP receptors but displays >1500-fold lower affinity for the canine and rat receptors as detd. via 125I-human CGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to det. the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concn.-dependent inhibition of dermal vasodilation, generated by capsaicin-induced release of endogenous CGRP, with plasma concns. of 127 and 994 nM required to block 50 and 90% of the blood flow increase, resp. In conclusion, MK-0974 is a highly potent, selective, and orally bioavailable CGRP receptor antagonist, which may be valuable in the acute treatment of migraine.
- 129Paone, D. V.; Nguyen, D. N.; Shaw, A. W.; Burgey, C. S.; Potteiger, C. M.; Deng, J. Z.; Mosser, S. D.; Salvatore, C. A.; Yu, S.; Roller, S.; Kane, S. A.; Selnick, H. G.; Vacca, J. P.; Williams, T. M. Orally bioavailable imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor antagonists: discovery of MK-2918. Bioorg. Med. Chem. Lett. 2011, 21, 2683– 2686, DOI: 10.1016/j.bmcl.2010.12.054[Crossref], [PubMed], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltFKitrc%253D&md5=71e7e25113bfb1b2ebe33dd6b07404e9Orally bioavailable imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor antagonists: Discovery of MK-2918Paone, Daniel V.; Nguyen, Diem N.; Shaw, Anthony W.; Burgey, Christopher S.; Potteiger, Craig M.; Deng, James Z.; Mosser, Scott D.; Salvatore, Christopher A.; Yu, Sean; Roller, Shane; Kane, Stefanie A.; Selnick, Harold G.; Vacca, Joseph P.; Williams, Theresa M.Bioorganic & Medicinal Chemistry Letters (2011), 21 (9), 2683-2686CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compd. with a lower projected clin. dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary Me ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclin. candidate 30 (MK-2918)(I).
- 130Peese, K. M.; Naidu, B. N.; Patel, M.; Li, C.; Langley, D. R.; Terry, B.; Protack, T.; Gali, V.; Lin, Z.; Samanta, H. K.; Zheng, M.; Jenkins, S.; Dicker, I. B.; Krystal, M. R.; Meanwell, N. A.; Walker, M. A. Heterocycle amide isosteres: an approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors. Bioorg. Med. Chem. Lett. 2020, 30, 126784, DOI: 10.1016/j.bmcl.2019.126784[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1eksr3I&md5=671f1b13aa1254656beda5d0fabba062Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitorsPeese, Kevin M.; Narasimhulu Naidu, B.; Patel, Manoj; Li, Chen; Langley, David R.; Terry, Brian; Protack, Tricia; Gali, Volodymyr; Lin, Zeyu; Samanta, Himadri K.; Zheng, Ming; Jenkins, Susan; Dicker, Ira B.; Krystal, Mark R.; Meanwell, Nicholas A.; Walker, Michael A.Bioorganic & Medicinal Chemistry Letters (2020), 30 (3), 126784CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepd. and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety is the optimal amide substitute and the obsd. activity was rationalized using calcd. properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compds. demonstrated moderate clearance and moderate exposure.
- 131Oliveira, M.; Ibanescu, R. I.; Anstett, K.; Mesplede, T.; Routy, J. P.; Robbins, M. A.; Brenner, B. G. The Montreal Primary HIV (PHI) Cohort Study Group; Selective resistance profiles emerging in patient-derived clinical isolates with cabotegravir, bictegravir, dolutegravir, and elvitegravir. Retrovirology 2018, 15, 56, DOI: 10.1186/s12977-018-0440-3[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjsFGntb4%253D&md5=6963c313565df2078500215620e9e84dSelective resistance profiles emerging in patient-derived clinical isolates with cabotegravir, bictegravir, dolutegravir, and elvitegravirOliveira, Maureen; Ibanescu, Ruxandra-Ilinca; Anstett, Kaitlin; Mesplede, Thibault; Routy, Jean-Pierre; Robbins, Marjorie A.; Brenner, Bluma G.Retrovirology (2018), 15 (), 56/1-56/14CODEN: RETRBO; ISSN:1742-4690. (BioMed Central Ltd.)Background: Integrase strand transfer inhibitors (INSTIs) are recommended for first-line HIV therapy based on their relatively high genetic barrier to resistance. Although raltegravir (RAL) and elvitegravir (EVG) resistance profiles are well-characterized, resistance patterns for dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) remain largely unknown. Here, in vitro drug selections compared the development of resistance to DTG, BIC, CAB, EVG and RAL using clin. isolates from treatment-na.ovrddot.ive primary HIV infection (PHI) cohort participants (n = 12), and pNL4.3 recombinant strains encoding patient-derived Integrase with (n = 5) and without (n = 5) the E157Q substitution. Results: Patient-derived viral isolates were serially passaged in PHA-stimulated cord blood mononuclear cells in the presence of escalating concns. of INSTIs over the course of 36-46 wk. Drug resistance arose more rapidly in primary clin. isolates with EVG (12/12), followed by CAB (8/12), DTG (8/12) and BIC (6/12). For pNL4.3 recombinant strains encoding patient-derived integrase, the comparative genetic barrier to resistance was RAL > EVG > CAB > DTG and BIC. The E157Q substitution in integrase delayed the advent of resistance to INSTIs. With EVG, T66I/A, E92G/V/Q, T97A or R263K (n = 16, 3, 2 and 1, resp.) arose by weeks 8-16, followed by 1-4 accessory mutations, conferring high-level resistance (> 100-fold) by week 36. With DTG and BIC, solitary R263K (n = 27), S153F/Y (n = 7) H51Y (n = 2), Q146 R (n = 3) or S147G (n = 1) mutations conferred low-level (< 3-fold) resistance at weeks 36-46. Similarly, most CAB selections (n = 18) resulted in R263K, S153Y, S147G, H51Y, or Q146L solitary mutations. However, three CAB selections resulted in Q148R/K followed by secondary mutations conferring high-level cross-resistance to all INSTIs. EVG-resistant viruses (T66I/R263K, T66I/E157Q/R263K, and S153A/R263K) retained residual susceptibility when switched to DTG, BIC or CAB, losing T66I by week 27. Two EVG-resistant variants developed resistance to DTG, BIC and CAB through the addnl. acquisition of E138A/Q148R and S230N, resp. One EVG-resistant variant (T66I) acquired L74M/ G140S/S147G, L74M/E138K/S147G and H51Y with DTG CAB and BIC, resp. Conclusions: Second generation INSTIs show a higher genetic barrier to resistance than EVG and RAL. The potency of CAB was lower than BIC and DTG. The development of Q148R/K with CAB can result in high-level cross-resistance to all INSTIs.
- 132Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Gonzalez Paz, O.; Hazuda, D. J.; Jones, P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.; Witmer, M. V.; Rowley, M. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J. Med. Chem. 2008, 51, 5843– 5855, DOI: 10.1021/jm800245z[ACS Full Text], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVymtb%252FM&md5=f90f994c7cd031a4063cbb3e91b4c3f0Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS InfectionSumma, Vincenzo; Petrocchi, Alessia; Bonelli, Fabio; Crescenzi, Benedetta; Donghi, Monica; Ferrara, Marco; Fiore, Fabrizio; Gardelli, Cristina; Gonzalez Paz, Odalys; Hazuda, Daria J.; Jones, Philip; Kinzel, Olaf; Laufer, Ralph; Monteagudo, Edith; Muraglia, Ester; Nizi, Emanuela; Orvieto, Federica; Pace, Paola; Pescatore, Giovanna; Scarpelli, Rita; Stillmock, Kara; Witmer, Marc V.; Rowley, MichaelJournal of Medicinal Chemistry (2008), 51 (18), 5843-5855CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these mols. were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclin. species. The good profile of Raltegravir has enabled its progression toward the end of phase III clin. trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.
- 133Naidu, B. N.; Walker, M. A.; Sorenson, M. E.; Ueda, Y.; Matiskella, J. D.; Connolly, T. P.; Dicker, I. B.; Lin, Z.; Bollini, S.; Terry, B. J.; Higley, H.; Zheng, M.; Parker, D. D.; Wu, D.; Adams, S.; Krystal, M. R.; Meanwell, N. A. The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor. Bioorg. Med. Chem. Lett. 2018, 28, 2124– 2130, DOI: 10.1016/j.bmcl.2018.05.027[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvVKjur8%253D&md5=92cf04a143ca99ed7950220c91945e79The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitorNaidu, B. Narasimhulu; Walker, Michael A.; Sorenson, Margaret E.; Ueda, Yasutsugu; Matiskella, John D.; Connolly, Timothy P.; Dicker, Ira B.; Lin, Zeyu; Bollini, Sagarika; Terry, Brian J.; Higley, Helen; Zheng, Ming; Parker, Dawn D.; Wu, Dedong; Adams, Stephen; Krystal, Mark R.; Meanwell, Nicholas A.Bioorganic & Medicinal Chemistry Letters (2018), 28 (12), 2124-2130CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal x-ray structure of compd. 10 (I). It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a satd. C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal x-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclin. profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clin. trials.
- 134Tracz-Gaszewska, Z.; Dobrzyn, P. Stearoyl-CoA desaturase 1 as a therapeutic target for the treatment of cancer. Cancers 2019, 11, 948, DOI: 10.3390/cancers11070948[Crossref], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjtlCksbk%253D&md5=e874e723b747233686121d95448e5898Stearoyl-CoA desaturase 1 as a therapeutic target for the treatment of cancerTracz-Gaszewska, Zuzanna; Dobrzyn, PawelCancers (2019), 11 (7), 948CODEN: CANCCT; ISSN:2072-6694. (MDPI AG)A distinctive feature of cancer cells of various origins involves alterations of the compn. of lipids, with significant enrichment in monounsatd. fatty acids. These mols., in addn. to being structural components of newly formed cell membranes of intensely proliferating cancer cells, support tumorigenic signaling. An increase in the expression of stearoyl-CoA desaturase 1 (SCD1), the enzyme that converts satd. fatty acids to Δ9-monounsatd. fatty acids, has been obsd. in a wide range of cancer cells, and this increase is correlated with cancer aggressiveness and poor outcomes for patients. Studies have demonstrated the involvement of SCD1 in the promotion of cancer cell proliferation, migration, metastasis, and tumor growth. Many studies have reported a role for this lipogenic factor in maintaining the characteristics of cancer stem cells (i.e., the population of cells that contributes to cancer progression and resistance to chemotherapy). Importantly, both the products of SCD1 activity and its direct impact on tumorigenic pathways have been demonstrated. Based on these findings, SCD1 appears to be a significant player in the development of malignant disease and may be a promising target for anticancer therapy. Numerous chem. compds. that exert inhibitory effects on SCD1 have been developed and preclinically tested. The present review summarizes our current knowledge of the ways in which SCD1 contributes to the progression of cancer and discusses opportunities and challenges of using SCD1 inhibitors for the treatment of cancer.
- 135Sun, S.; Zhang, Z.; Kodumuru, V.; Pokrovskaia, N.; Fonarev, J.; Jia, Q.; Leung, P. Y.; Tran, J.; Ratkay, L. G.; McLaren, D. G.; Radomski, C.; Chowdhury, S.; Fu, J.; Hubbard, B.; Winther, M. D.; Dales, N. A. Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseases. Bioorg. Med. Chem. Lett. 2014, 24, 520– 525, DOI: 10.1016/j.bmcl.2013.12.036[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXms1ah&md5=0e63c760d701fe2e88eeb8ff337d0268Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseasesSun, Shaoyi; Zhang, Zaihui; Kodumuru, Vishnumurthy; Pokrovskaia, Natalia; Fonarev, Julia; Jia, Qi; Leung, Po-Yee; Tran, Jennifer; Ratkay, Leslie G.; McLaren, David G.; Radomski, Chris; Chowdhury, Sultan; Fu, Jianmin; Hubbard, Brian; Winther, Michael D.; Dales, Natalie A.Bioorganic & Medicinal Chemistry Letters (2014), 24 (2), 520-525CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Several five- and six-membered heterocycles were introduced to replace the C2-position amide bond of the original 2-aminothiazole-based hit compd. Specifically, replacement of the amide bond with an imidazolidinone moiety yielded a novel and potent thiazolylimidazolidinone series of SCD1 inhibitors. XEN723 I was identified after optimization of the thiazolylimidazolidinone series. This compd. demonstrated a 560-fold improvement in in vitro potency and reduced plasma desatn. indexes in a dose dependent manner, with an EC50 of 4.5 mg/kg.
- 136Ballatore, C.; Huryn, D. M.; Smith, A. B., 3rd Carboxylic acid (bio)isosteres in drug design. ChemMedChem 2013, 8, 385– 395, DOI: 10.1002/cmdc.201200585[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFCms7g%253D&md5=cff8233af1c386439789a0e4ebcb4331Carboxylic Acid (Bio)Isosteres in Drug DesignBallatore, Carlo; Huryn, Donna M.; Smith, Amos B.ChemMedChem (2013), 8 (3), 385-395CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant drawbacks, including metabolic instability, toxicity, as well as limited passive diffusion across biol. membranes. To avoid some of these shortcomings while retaining the desired attributes of the carboxylic acid moiety, medicinal chemists often investigate the use of carboxylic acid (bio)isosteres. The same type of strategy can also be effective for a variety other purposes, for example, to increase the selectivity of a biol. active compd. or to create new intellectual property. Several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this strategy is generally found to be dependent upon the particular context (i.e., the characteristic properties of the drug and the drug-target). As a result, screening of a panel of isosteres is typically required. In this context, the discovery and development of novel carboxylic acid surrogates that could complement the existing palette of isosteres remains an important area of research. The goal of this Minireview is to provide an overview of the most commonly employed carboxylic acid (bio)isosteres and to present representative examples demonstrating the use and utility of each isostere in drug design.
- 137Subramanian, V.; Knight, J. S.; Parelkar, S.; Anguish, L.; Coonrod, S. A.; Kaplan, M. J.; Thompson, P. R. Design, synthesis, and biological evaluation of tetrazole analogs of Cl-amidine as protein arginine deiminase inhibitors. J. Med. Chem. 2015, 58, 1337– 1344, DOI: 10.1021/jm501636x[ACS Full Text], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivFSrsA%253D%253D&md5=f8dbecee72a82061038671d5190635deDesign, Synthesis, and Biological Evaluation of Tetrazole Analogs of Cl-Amidine as Protein Arginine Deiminase InhibitorsSubramanian, Venkataraman; Knight, Jason S.; Parelkar, Sangram; Anguish, Lynne; Coonrod, Scott A.; Kaplan, Mariana J.; Thompson, Paul R.Journal of Medicinal Chemistry (2015), 58 (3), 1337-1344CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Protein arginine deiminases (PADs) catalyze the post-translational hydrolysis of arginine residues to form citrulline. This once obscure modification is now known to play a key role in the etiol. of multiple autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, lupus, and ulcerative colitis) and in some forms of cancer. Among the five human PADs (PAD1, -2, -3, -4, and -6), it is unclear which isoenzyme contributes to disease pathogenesis. Toward the identification of potent, selective, and bioavailable PAD inhibitors that can be used to elucidate the specific roles of each isoenzyme, we describe tetrazole analogs as suitable backbone amide bond bioisosteres for the parent pan PAD inhibitor Cl-amidine. These tetrazole based analogs are highly potent and show selectivity toward particular isoenzymes. Importantly, one of the compds., biphenyl tetrazole tert-Bu Cl-amidine (compd. 13), exhibits enhanced cell killing in a PAD4 expressing osteosarcoma bone marrow (U2OS) cell line and can also block the formation of neutrophil extracellular traps. These bioisosteres represent an important step in our efforts to develop stable, bioavailable, and selective inhibitors for the PADs.
- 138Witalison, E. E.; Thompson, P. R.; Hofseth, L. J. Protein arginine deiminases and associated citrullination: physiological functions and diseases associated with dysregulation. Curr. Drug Targets 2015, 16, 700– 710, DOI: 10.2174/1389450116666150202160954[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFSht7vJ&md5=9d0072b3b5e23308858bb4cd4ed0cab7Protein Arginine Deiminases and Associated Citrullination: Physiological Functions and Diseases Associated with DysregulationWitalison, Erin E.; Thompson, Paul R.; Hofseth, Lorne J.Current Drug Targets (2015), 16 (7), 700-710CODEN: CDTUAU; ISSN:1389-4501. (Bentham Science Publishers Ltd.)Human proteins are subjected to more than 200 known post-translational modifications (PTMs) (e.g., phosphorylation, glycosylation, ubiquitination, S-nitrosylation, methylation, Nacetylation, and citrullination) and these PTMs can alter protein structure and function with consequent effects on the multitude of pathways necessary for maintaining the physiol. homeostasis. When dysregulated, however, the enzymes that catalyze these PTMs can impact the genesis of countless diseases. In this review, we will focus on protein citrullination, a PTM catalyzed by the Protein Arginine Deiminase (PAD) family of enzymes. Specifically, we will describe the roles of the PADs in both normal human physiol. and disease. The development of PAD inhibitors and their efficacy in a variety of autoimmune disorders and cancer will also be discussed.
- 139Leshner, M.; Wang, S.; Lewis, C.; Zheng, H.; Chen, X. A.; Santy, L.; Wang, Y. PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Front. Immunol. 2012, 3, 307, DOI: 10.3389/fimmu.2012.00307[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s%252Fks1yhtQ%253D%253D&md5=869e8c6330ed07151894fe61b331be8ePAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structuresLeshner Marc; Wang Shu; Lewis Carrie; Zheng Han; Chen Xiangyun Amy; Santy Lorraine; Wang YanmingFrontiers in immunology (2012), 3 (), 307 ISSN:.NETosis, the process wherein neutrophils release highly decondensed chromatin called neutrophil extracellular traps (NETs), has gained much attention as an alternative means of killing bacteria. In vivo, NETs are induced by bacteria and pro-inflammatory cytokines. We have reported that peptidylarginine deiminase 4 (PAD4), an enzyme that converts Arg or monomethyl-Arg to citrulline in histones, is essential for NET formation. The areas of extensive chromatin decondensation along the NETs were rich in histone citrullination. Here, upon investigating the effect of global citrullination in cultured cells, we discovered that PAD4 overexpression in osteosarcoma U2OS cells induces extensive chromatin decondensation independent of apoptosis. The highly decondensed chromatin is released to the extracellular space and stained strongly by a histone citrulline-specific antibody. The structure of the decondensed chromatin is reminiscent of NETs but is unique in that it occurs without stimulation of cells with pro-inflammatory cytokines and bacteria. Furthermore, histone citrullination during chromatin decondensation can dissociate heterochromatin protein 1 beta (HP1β) thereby offering a new molecular mechanism for understanding how citrullination regulates chromatin function. Taken together, our study suggests that PAD4 mediated citrullination induces chromatin decondensation, implicating its essential role in NET formation under physiological conditions in neutrophils.
- 140Khandpur, R.; Carmona-Rivera, C.; Vivekanandan-Giri, A.; Gizinski, A.; Yalavarthi, S.; Knight, J. S.; Friday, S.; Li, S.; Patel, R. M.; Subramanian, V.; Thompson, P.; Chen, P.; Fox, D. A.; Pennathur, S.; Kaplan, M. J. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl. Med. 2013, 5, 178ra40, DOI: 10.1126/scitranslmed.3005580
- 141Han, D.; Handelman, G.; Marcocci, L.; Sen, C. K.; Roy, S.; Kobuchi, H.; Tritschler, H. J.; Flohe, L.; Packer, L. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. BioFactors 1997, 6, 321– 338, DOI: 10.1002/biof.5520060303[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmtVyqu74%253D&md5=87df895d501180c5d14056ff61ccb48aLipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilizationHan, Derick; Handelman, Garry; Marcocci, Lucia; Sen, Chandan K.; Roy, Sashwati; Kobuchi, Hirotsugu; Tritschler, Hans J.; Flohe, Leopold; Packer, LesterBioFactors (1997), 6 (3), 321-338CODEN: BIFAEU; ISSN:0951-6433. (IOS Press)Lipoic acid (thiotic acid) is being used as a dietary supplement, and as a therapeutic agent, and is reported to have beneficial effects in disorders assocd. with oxidative stress, but its mechanism of action remains unclear. We present evidence that lipoic acid induces a substantial increase in cellular reduced glutathione in cultured human Jurkat T cells, human erythrocytes, C6 glial cells, NB41A3 neuroblastoma cells, and peripheral blood lymphocytes. The effect depends on metabolic redn. of lipoic acid to dihydrolipoic acid. Dihydrolipoic acid is released into the culture medium where it reduces cystine. Cysteine thus formed is readily taken up by the neutral amino acid transport system and utilized for glutathione synthesis. By this mechanism lipoic acid enables cystine to bypass the xc- transport system, which is weakly expressed in lymphocytes and inhibited by glutamate. Thereby lipoic acid enables the key enzyme of glutathione synthesis, γ-glutamylcysteine synthetase, which is regulated by uptake-limited cysteine supply, to work at optimum conditions. Flow cytometric anal. of freshly prepd. human peripheral blood lymphocytes, using monobromobimane labeling of cellular thiols, reveals that lipoic acid acts mainly to normalize a subpopulation of cells severely compromised in thiol status rather than to increase thiol content beyond physiol. levels. Hence lipoic acid may have clin. relevance in restoration of severely glutathione deficient cells.
- 142Podda, M.; Tritschler, H. J.; Ulrich, H.; Packer, L. α-lipoic acid supplementation prevents symptoms of vitamin E deficiency. Biochem. Biophys. Res. Commun. 1994, 204, 98– 104, DOI: 10.1006/bbrc.1994.2431[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmsFCnur8%253D&md5=2fb6543fbbc7f90930fa04d3a2af2a6eα-Lipoic acid supplementation prevents symptoms of vitamin E deficiencyPodda, M.; Tritschler, H. J.; Ulrich, H.; Packer, L.Biochemical and Biophysical Research Communications (1994), 204 (1), 98-109CODEN: BBRCA9; ISSN:0006-291X.In this study, using a new animal model for rapid vitamin E deficiency in adult animals and a new technique for tissue extn. of oxidized and reduced α-lipoic acid, we examd. the antioxidant action of α-lipoic acid in vivo. Vitamin E-deficient adult hairless mice displayed obvious symptoms of deficiency with in five weeks, but if the diet was supplemented with α-lipoic acid the animals were completely protected. At five weeks on a vitamin E-deficient diet animals exhibited similar decreases in tissue vitamin E levels, whether supplemented or unsupplemented with α-lipoic acid: vitamin E levels in lvier, kidney, heart, and skin decreased 70 to 85% ppm levels in brain decreased only 25%. These data show that there was no effect of α-lipoic acid supplementation on vitamin E tissue concns., arguing against a role for α-lipoic acid in regenerating vitamin E in vivo.
- 143Rochette, L.; Ghibu, S.; Richard, C.; Zeller, M.; Cottin, Y.; Vergely, C. Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potential. Mol. Nutr. Food Res. 2013, 57, 114– 125, DOI: 10.1002/mnfr.201200608[Crossref], [PubMed], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjslehtw%253D%253D&md5=4692703b1b099b024b1fb4d19c811ab2Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potentialRochette, Luc; Ghibu, Steliana; Richard, Carole; Zeller, Marianne; Cottin, Yves; Vergely, CatherineMolecular Nutrition & Food Research (2013), 57 (1), 114-125CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Diabetes has emerged as a major threat to worldwide health. The exact mechanisms underlying the disease are unknown; however, there is growing evidence that the excess generation of reactive oxygen species (ROS) assocd. with hyperglycemia, causes oxidative stress in a variety of tissues. In this context, various natural compds. with pleiotropic actions like α-lipoic acid (LA) are of interest, esp. in metabolic diseases such as diabetes. LA, either as a dietary supplement or a therapeutic agent, modulates redox potential because of its ability to match the redox status between different subcellular compartments as well as extracellularly. Both the oxidized (disulfide) and reduced (di-thiol: dihydro-lipoic acid, DHLA) forms of LA show antioxidant properties. LA exerts antioxidant effects in biol. systems through ROS quenching but also via an action on transition metal chelation. Dietary supplementation with LA has been successfully employed in a variety of in vivo models of disease assocd. with an imbalance of redox status: diabetes and cardiovascular diseases. The complex and intimate assocn. between increased oxidative stress and increased inflammation in related disorders such as diabetes, makes it difficult to establish the temporal sequence of the relationship.
- 144Koufaki, M.; Kiziridi, C.; Nikoloudaki, F.; Alexis, M. N. Design and synthesis of 1,2-dithiolane derivatives and evaluation of their neuroprotective activity. Bioorg. Med. Chem. Lett. 2007, 17, 4223– 4227, DOI: 10.1016/j.bmcl.2007.05.036[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnsVKnt7c%253D&md5=16d177172281188d616980f44c7b35f1Design and synthesis of 1,2-dithiolane derivatives and evaluation of their neuroprotective activityKoufaki, Maria; Kiziridi, Christina; Nikoloudaki, Faidra; Alexis, Michael N.Bioorganic & Medicinal Chemistry Letters (2007), 17 (15), 4223-4227CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)The authors designed and synthesized new analogs contg. 1,2-dithiolane-3-alkyl and protected or free catechol moieties connected through heteroarom. rings such as triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, tetrazole or thiazole to explore the influence of the bioisosteric replacement of the amide group on the neuroprotective activity of the lipoic acid/dopamine conjugate. Evaluation of the activity of the new compds., using glutamate-challenged hippocampal HT22 cells, showed that incorporation of heteroarom. rings in the alkyl-1,2-dithiolane moieties in conjunction with another antioxidant, in this case catechol, may result in strong neuroprotective activity.
- 145Dani, J. A. Neuronal nicotinic acetylcholine receptor structure and function and response to nicotine. Int. Rev. Neurobiol. 2015, 124, 3– 19, DOI: 10.1016/bs.irn.2015.07.001[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXptlWrtL0%253D&md5=60e9464071be064fd9c669df2f475cbaNeuronal nicotinic acetylcholine receptor structure and function and response to nicotineDani, John A.International Review of Neurobiology (2015), 124 (Nicotine Use in Mental Illness and Neurological Disorders), 3-19CODEN: IRNEAE; ISSN:0074-7742. (Elsevier)Nicotinic acetylcholine receptors (nAChRs) belong to the "Cys-loop" superfamily of ligand-gated ion channels that includes GABAA, glycine, and serotonin (5-HT3) receptors. There are 16 homologous mammalian nAChR subunits encoded by a multigene family. These subunits combine to form many different nAChR subtypes with various expression patterns, diverse functional properties, and differing pharmacol. characteristics. Because cholinergic innervation is pervasive and nAChR expression is extremely broad, practically every area of the brain is impinged upon by nicotinic mechanisms. This review briefly examines the structural and functional properties of the receptor/channel complex Itself. The review also summarizes activation and desensitization of nAChRs by the low nicotine concns. obtained from tobacco. Knowledge of the three-dimensional structure and the structural characteristics of channel gating has reached an advanced stage. Likewise, the basic functional properties of the channel also are reasonably well understood. It is these receptor/channel properties that underlie the participation of nAChRs in nearly every anatomical region of the mammalian brain.
- 146Feduccia, A. A.; Chatterjee, S.; Bartlett, S. E. Neuronal nicotinic acetylcholine receptors: neuroplastic changes underlying alcohol and nicotine addictions. Front. Mol. Neurosci. 2012, 5, 83, DOI: 10.3389/fnmol.2012.00083[Crossref], [PubMed], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Git7zM&md5=6857f2dac6c88f9d336911716c831123Neuronal nicotinic acetylcholine receptors: neuroplastic changes underlying alcohol and nicotine addictionsFeduccia, Allison A.; Chatterjee, Susmita; Bartlett, Selena E.Frontiers in Molecular Neuroscience (2012), 5 (Aug.), 83CODEN: FMNRAJ; ISSN:1662-5099. (Frontiers Media S.A.)A review. Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent mol. mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common mol. target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the mol. and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies.
- 147Buckingham, S. D.; Jones, A. K.; Brown, L. A.; Sattelle, D. B. Nicotinic acetylcholine receptor signalling: roles in Alzheimer’s disease and amyloid neuroprotection. Pharmacol. Rev. 2009, 61, 39– 61, DOI: 10.1124/pr.108.000562[Crossref], [PubMed], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXkvVKjuro%253D&md5=7513d8ea11ac6001401c938d98d0ab84Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotectionBuckingham, Steven D.; Jones, Andrew K.; Brown, Laurence A.; Sattelle, David B.Pharmacological Reviews (2009), 61 (1), 39-61CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. Alzheimer's disease (AD), the major contributor to dementia in the elderly, involves accumulation in the brain of extracellular plaques contg. the β-amyloid protein (Aβ) and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is also characterized by a loss of neurons, particularly those expressing nicotinic acetylcholine receptors (nAChRs), thereby leading to a redn. in nAChR nos. The Aβ1-42 protein, which is toxic to neurons, is crit. to the onset and progression of AD. The discovery of new drug therapies for AD is likely to be accelerated by an improved understanding of the mechanisms whereby Aβ causes neuronal death. We examine the evidence for a role in Aβ1-42 toxicity of nAChRs; paradoxically, nAChRs can also protect neurons when activated by nicotinic ligands. Aβ peptides and nicotine differentially activate several intracellular signaling pathways, including the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog pathway, the extracellular signal-regulated kinase/mitogen-activated protein kinase, and JAK-2/STAT-3 pathways. These pathways control cell death or survival and the secretion of Aβ peptides. We propose that understanding the differential activation of these pathways by nicotine and/or Aβ1-42 may offer the prospect of new routes to therapy for AD.
- 148Woodruff-Pak, D. S.; Gould, T. J. Neuronal nicotinic acetylcholine receptors: involvement in Alzheimer’s disease and schizophrenia. Behav. Cogn. Neurosci. Rev. 2002, 1, 5– 20, DOI: 10.1177/1534582302001001002[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2svps12qtA%253D%253D&md5=a85db74fd91f39e41b17a825662e84aeNeuronal nicotinic acetylcholine receptors: involvement in Alzheimer's disease and schizophreniaWoodruff-Pak Diana S; Gould Thomas JBehavioral and cognitive neuroscience reviews (2002), 1 (1), 5-20 ISSN:1534-5823.Nicotinic acetylcholine receptors (nAChRs) play a role in a variety of diseases of the central nervous system including Alzheimer's disease (AD) and schizophrenia. There is great interest in evaluating disease-related nA ChR changes, and pharmacological treatment of nAChR deficits is a promising therapy. In AD, 7 nAChRs remain relatively stable, contrasting to 4 2 nAChRs that are lost in substantial numbers. -amyloid, a major neuropathology in AD, blocks 4 2 and 7 nAChRs. Agonists selective to 7nAChRs are neuroprotective against--amyloid. Paradoxically, 7nAChRs may function as receptors for -amyloid. These results indicate 7 nAChR antagonists may be appropriate therapy in AD. In schizophrenia, 7 nAChRs are significantly reduced in hippocampus and neocortex. The exceptionally high rate of smoking in schizophrenics is likely a form of self-medication. Therapy with 7 nAChR agonists relieves some schizophrenic symptoms. Despite disparities in etiology and symptomatology, AD and schizophrenia share a target for therapeutic intervention--7 nAChRs.
- 149Beinat, C.; Reekie, T.; Hibbs, D.; Xie, T.; Olson, T. T.; Xiao, Y.; Harvey, A.; O’Connor, S.; Coles, C.; Tsanaktsidis, J.; Kassiou, M. Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333. Eur. J. Med. Chem. 2014, 84, 200– 205, DOI: 10.1016/j.ejmech.2014.07.029[Crossref], [PubMed], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1GrsL7J&md5=5f60b164ac340eec75381dd333c1f465Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333Beinat, Corinne; Reekie, Tristan; Hibbs, David; Xie, Teresa; Olson, Thao T.; Xiao, Yingxian; Harvey, Andrew; O'Connor, Susan; Coles, Carolyn; Tsanaktsidis, John; Kassiou, MichaelEuropean Journal of Medicinal Chemistry (2014), 84 (), 200-205CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Several lines of exptl. evidence support the involvement of the α7 nAChR in schizophrenia and Alzheimer's disease. Modulators of the α7 nAChR have been extensively reviewed for the treatment of the cognitive deficits assocd. with these pathologies. SEN12333 represents a novel α7 nAChR agonist chemotype with potential for reduced side effects but requiring further SAR exploration. The present work investigates the amide bond of SEN12333, specifically its connectivity and replacement with the tetrazole functionality, a known cis amide isostere. The results reveal the original amide bond connectivity of SEN12333 to be favorable for binding affinity and agonist activity at α7 nAChRs. The use of a tetrazole isostere completely abolishes affinity and functional activity and suggests that SEN12333 binds in a linear conformation. Results reported herein also suggest the pyridine nitrogen within the terminal arom. ring of SEN12333 is not essential for binding affinity or functional activity. Further SAR investigations involving manipulation of other moieties contained within SEN12333 are warranted.
- 150Haydar, S. N.; Ghiron, C.; Bettinetti, L.; Bothmann, H.; Comery, T. A.; Dunlop, J.; La Rosa, S.; Micco, I.; Pollastrini, M.; Quinn, J.; Roncarati, R.; Scali, C.; Valacchi, M.; Varrone, M.; Zanaletti, R. SAR and biological evaluation of SEN12333/WAY-317538: novel alpha 7 nicotinic acetylcholine receptor agonist. Bioorg. Med. Chem. 2009, 17, 5247– 5258, DOI: 10.1016/j.bmc.2009.05.040[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosVyqsrk%253D&md5=293ee7e518e64386330cfde5ca72c584SAR and biological evaluation of SEN12333/WAY-317538: Novel alpha 7 nicotinic acetylcholine receptor agonistHaydar, Simon N.; Ghiron, Chiara; Bettinetti, Laura; Bothmann, Hendrick; Comery, Thomas A.; Dunlop, John; La Rosa, Salvatore; Micco, Iolanda; Pollastrini, Martina; Quinn, Joanna; Roncarati, Renza; Scali, Carla; Valacchi, Michela; Varrone, Maurizio; Zanaletti, RiccardoBioorganic & Medicinal Chemistry (2009), 17 (14), 5247-5258CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment assocd. with a variety of disorders including Alzheimer's disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions assocd. with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer's disease. Herein we report a novel, potent small mol. agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compd. is a selective agonist of the α7 nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioral cognition models. The SAR and biol. evaluation of this series of compds. are discussed.
- 151Beinat, C.; Banister, S. D.; van Prehn, S.; Doddareddy, M. R.; Hibbs, D.; Sako, M.; Chebib, M.; Tran, T.; Al-Muhtasib, N.; Xiao, Y.; Kassiou, M. Consequences of linker length alteration of the α7 nicotinic acetylcholine receptor (nAChR) agonist, SEN12333. Bioorg. Med. Chem. Lett. 2012, 22, 2380– 2384, DOI: 10.1016/j.bmcl.2012.02.052[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1yit7s%253D&md5=b17ce649cb8de8749c1f3e0b7c8f1c0cConsequences of linker length alteration of the α7 nicotinic acetylcholine receptor (nAChR) agonist, SEN12333Beinat, Corinne; Banister, Samuel D.; van Prehn, Saundra; Doddareddy, Munikumar Reddy; Hibbs, David; Sako, Michael; Chebib, Mary; Tran, Thao; Al-Muhtasib, Nour; Xiao, Yingxian; Kassiou, MichaelBioorganic & Medicinal Chemistry Letters (2012), 22 (7), 2380-2384CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of ligands based on SEN12333, contg. either contracted or elongated alkyl chains, were synthesized and evaluated in mol. docking studies against a homol. model of the α7 nicotinic acetylcholine receptor (nAChR) subtype. The predicted binding of all ligands was highly similar, with the exception of the analog contg. a 5 methylene unit spacer. However, in vitro competition binding assays revealed that the ligands possessed dissimilar binding affinities, with a Ki range of more than an order of magnitude (Ki = 0.50 to >10 μM), and only SEN12333 itself exhibited functional activity at the α7 nAChR.
- 152Graham, T. H. Prolylcarboxypeptidase (PrCP) inhibitors and the therapeutic uses thereof: a patent review. Expert Opin. Ther. Pat. 2017, 27, 1077– 1088, DOI: 10.1080/13543776.2017.1349104[Crossref], [PubMed], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFKrsbjL&md5=33327e2a7245983dc60f403c31a51313Prolylcarboxypeptidase (PrCP) inhibitors and the therapeutic uses thereof: a patent reviewGraham, Thomas H.Expert Opinion on Therapeutic Patents (2017), 27 (10), 1077-1088CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.): Prolylcarboxypeptidase (PrCP) is a serine protease that produces or degrades signaling proteins in several important pathways including the renin-angiotensin system (RAS), kallikrein-kinin system (KKS) and pro-opiomelanocortin (POMC) system. PrCP has the potential to be a therapeutic target for cardiovascular, inflammatory and metabolic diseases. Numerous classes of PrCP inhibitors have been developed by rational drug design and from high-throughput screening hits. These inhibitors have been tested in mouse models to assess their potential as new therapeutics.:. This review covers the relevant studies that support PrCP as a target for drug discovery. All the significant patent applications and primary literature concerning the development of PrCP inhibitors are discussed. The pathways where PrCP is known to operate are complex and many aspects remain to be characterized. Many potent inhibitors of PrCP have been tested in vivo. The variable results obtained from in vivo studies with PrCP inhibitors suggest that addnl. understanding of the biochem. and the required therapeutic inhibitor levels is necessary. Addnl. fundamental research into the signaling pathways is likely required before the true therapeutic potential of PrCP inhibition will be realized.
- 153Shen, H. C.; Ding, F. X.; Zhou, C.; Xiong, Y.; Verras, A.; Chabin, R. M.; Xu, S.; Tong, X.; Xie, D.; Lassman, M. E.; Bhatt, U. R.; Garcia-Calvo, M. M.; Geissler, W.; Shen, Z.; Chen, D.; Sinharoy, R.; Hale, J. J.; Tata, J. R.; Pinto, S.; Shen, D. M.; Colletti, S. L. Discovery of benzimidazole pyrrolidinyl amides as prolylcarboxypeptidase inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 1299– 1305, DOI: 10.1016/j.bmcl.2011.01.090[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXit1Gmt7w%253D&md5=fd1156e6baf01e5a28a062f56c1d627dDiscovery of benzimidazole pyrrolidinyl amides as prolylcarboxypeptidase inhibitorsShen, Hong C.; Ding, Fa-Xiang; Zhou, Changyou; Xiong, Yusheng; Verras, Andreas; Chabin, Renee M.; Xu, Suoyu; Tong, Xinchun; Xie, Dan; Lassman, Michael E.; Bhatt, Urmi R.; Garcia-Calvo, Margarita M.; Geissler, Wayne; Shen, Zhu; Chen, Dunlu; SinhaRoy, Ranabir; Hale, Jeffery J.; Tata, James R.; Pinto, Shirly; Shen, Dong-Ming; Colletti, Steven L.Bioorganic & Medicinal Chemistry Letters (2011), 21 (5), 1299-1305CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of benzimidazole pyrrolidinyl amides contg. a piperidinyl group were discovered as novel prolylcarboxypeptidase (PrCP) inhibitors. Low-nanomolar IC50's were achieved for several analogs, of which compd. 9b displayed modest ex vivo target engagement in eDIO mouse plasma. Compd. 9b was also studied in vivo for its effect on wt. loss and food intake in an eDIO mouse model and the results will be discussed.
- 154Wu, Z.; Yang, C.; Xiong, Y.; Feng, Z.; Lombardo, M.; Verras, A.; Chabin, R. M.; Xu, S.; Tong, X.; Xie, D.; Lassman, M. E.; Bhatt, U. R.; Garcia-Calvo, M. M.; Geissler, W.; Shen, Z.; Chen, Q.; Sinharoy, R.; Hale, J. J.; Tata, J. R.; Pinto, S.; Shen, D. M.; Colletti, S. L. Discovery of a new class of potent prolylcarboxypeptidase inhibitors derived from alanine. Bioorg. Med. Chem. Lett. 2012, 22, 1774– 1778, DOI: 10.1016/j.bmcl.2011.12.064[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitVWqtbg%253D&md5=1fddce909d175a2c3752bf5e5fdc3856Discovery of a new class of potent prolylcarboxypeptidase inhibitors derived from alanineWu, Zhicai; Yang, Cangming; Xiong, Yusheng; Feng, Zhe; Lombardo, Matthew; Verras, Andreas; Chabin, Renee M.; Xu, Suoyu; Tong, Xinchun; Xie, Dan; Lassman, Mike E.; Bhatt, Urmi R.; Garcia-Calvo, Margarita M.; Geissler, Wayne; Shen, Zhu; Chen, Qing; Sinharoy, Ranabir; Hale, Jeffrey J.; Tata, James R.; Pinto, Shirly; Shen, Dong-Ming; Colletti, Steven L.Bioorganic & Medicinal Chemistry Letters (2012), 22 (4), 1774-1778CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Efforts to modify the central proline portion of lead compd. 4 lead to the discovery of novel prolylcarboxypeptidase (PrCP) inhibitors. Esp., replacement with alanine afforded compd. 19 displaying more potent human and mouse PrCP inhibitory activity than 4 and an overall comparable profile.
- 155Debenham, J. S.; Graham, T. H.; Verras, A.; Zhang, Y.; Clements, M. J.; Kuethe, J. T.; Madsen-Duggan, C.; Liu, W.; Bhatt, U. R.; Chen, D.; Chen, Q.; Garcia-Calvo, M.; Geissler, W. M.; He, H.; Li, X.; Lisnock, J.; Shen, Z.; Tong, X.; Tung, E. C.; Wiltsie, J.; Xu, S.; Hale, J. J.; Pinto, S.; Shen, D. M. Discovery and optimization of orally active cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 6228– 6233, DOI: 10.1016/j.bmcl.2013.09.094[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1yqs7bK&md5=4005750b675e71573f7a6167ed843ff8Discovery and optimization of orally active cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitorsDebenham, John S.; Graham, Thomas H.; Verras, Andreas; Zhang, Yong; Clements, Matthew J.; Kuethe, Jeffrey T.; Madsen-Duggan, Christina; Liu, Wensheng; Bhatt, Urmi R.; Chen, Dunlu; Chen, Qing; Garcia-Calvo, Margarita; Geissler, Wayne M.; He, Huaibing; Li, Xiaohua; Lisnock, Jean Marie; Shen, Zhu; Tong, Xinchun; Tung, Elaine C.; Wiltsie, Judyann; Xu, Suoyu; Hale, Jeffrey J.; Pinto, Shirly; Shen, Dong-MingBioorganic & Medicinal Chemistry Letters (2013), 23 (23), 6228-6233CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compds. e. g., I show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose.
- 156Graham, T. H.; Shu, M.; Verras, A.; Chen, Q.; Garcia-Calvo, M.; Li, X.; Lisnock, J.; Tong, X.; Tung, E. C.; Wiltsie, J.; Hale, J. J.; Pinto, S.; Shen, D. M. Pyrazoles as non-classical bioisosteres in prolylcarboxypeptidase (PrCP) inhibitors. Bioorg. Med. Chem. Lett. 2014, 24, 1657– 1660, DOI: 10.1016/j.bmcl.2014.02.070[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXksF2hsL0%253D&md5=52027c184087d4d3f3322031ebe065c0Pyrazoles as non-classical bioisosteres in prolylcarboxypeptidase (PrCP) inhibitorsGraham, Thomas H.; Shu, Min; Verras, Andreas; Chen, Qing; Garcia-Calvo, Margarita; Li, Xiaohua; Lisnock, JeanMarie; Tong, Xinchun; Tung, Elaine C.; Wiltsie, Judyann; Hale, Jeffrey J.; Pinto, Shirly; Shen, Dong-MingBioorganic & Medicinal Chemistry Letters (2014), 24 (7), 1657-1660CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Bioisosteres are integral components of modern pharmaceutical research that allow structural optimization to maximize in vivo efficacy and minimize adverse effects by selectively modifying pharmacodynamic, pharmacokinetic and physicochem. properties. A recent medicinal chem. campaign focused on identifying small mol. inhibitors of prolylcarboxypeptidase (PrCP) initiated an investigation into the use of pyrazoles as bioisosteres for amides. The results indicate that pyrazoles are suitable bioisosteric replacements of amide functional groups. The study is an example of managing bioisosteric replacement by incorporating subsequent structural modifications to maintain potency against the selected target. A heuristic model for an embedded pharmacophore is also described.
- 157Pacher, P.; Batkai, S.; Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 2006, 58, 389– 462, DOI: 10.1124/pr.58.3.2[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVOhtLfO&md5=f54e6d1303645a1c63809879ef2813f3The endocannabinoid system as an emerging target of pharmacotherapyPacher, Pal; Batkai, Sandor; Kunos, GeorgePharmacological Reviews (2006), 58 (3), 389-462CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metab. and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing no. of physiol. functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathol. conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metab. or transport. The use of selective CB2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of prepns. with controlled compn. and the careful selection of does and route of administration. The growing no. of preclin. studies and clin. trials with compds. that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a no. of diseases for which current treatments do not fully address the patients' need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.
- 158Pertwee, R. G. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos. Trans. R. Soc., B 2012, 367, 3353– 3363, DOI: 10.1098/rstb.2011.0381[Crossref], [PubMed], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVKgtL3L&md5=520dda552cdeb306560444cf7c5932f6Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilitiesPertwee, Roger G.Philosophical Transactions of the Royal Society, B: Biological Sciences (2012), 367 (1607), 3353-3363CODEN: PTRBAE; ISSN:0962-8436. (Royal Society)A review. Human tissues express cannabinoid CB1 and CB2 receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compds. in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB1/CB2 receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ9-tetrahydrocannabinol (Δ9-THC)) and Sativex (Δ9-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible addnl. therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB2 receptors, and/or (v) adjunctive 'multi-targeting'.
- 159Adam, J. M.; Cairns, J.; Caulfield, W.; Cowley, P.; Cumming, I.; Easson, M.; Edwards, D.; Ferguson, M.; Goodwin, R.; Jeremiah, F.; Kiyoi, T.; Mistry, A.; Moir, E.; Morphy, R.; Tierney, J.; York, M.; Baker, J.; Cottney, J. E.; Houghton, A. K.; Westwood, P. J.; Walker, G. Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists. MedChemComm 2010, 1, 54– 60, DOI: 10.1039/c0md00022a[Crossref], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVeju7vP&md5=0f84b46a18456470f5b4566b9922dbb3Design, synthesis, and structure-activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonistsAdam, Julia M.; Cairns, Jim; Caulfield, Wilson; Cowley, Phillip; Cumming, Iain; Easson, Morag; Edwards, Darren; Ferguson, Morag; Goodwin, Richard; Jeremiah, Fiona; Kiyoi, Takao; Mistry, Ashvin; Moir, Elizabeth; Morphy, Richard; Tierney, Jason; York, Mark; Baker, James; Cottney, Jean E.; Houghton, Andrea K.; Westwood, Paul J.; Walker, GlennMedChemComm (2010), 1 (1), 54-60CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A novel CB1 receptor agonist lead series was identified using a high-throughput screening approach. The initial screen afforded a single confirmed hit with poor water soly. Structural variations were explored with the aim of introducing water soly. and improving potency. This led to the discovery of Org 28611, a potent, water sol. CB1 receptor agonist, which was selected for clin. evaluation as a potential i.v. analgesic agent.
- 160Moir, E. M.; Yoshiizumi, K.; Cairns, J.; Cowley, P.; Ferguson, M.; Jeremiah, F.; Kiyoi, T.; Morphy, R.; Tierney, J.; Wishart, G.; York, M.; Baker, J.; Cottney, J. E.; Houghton, A. K.; McPhail, P.; Osprey, A.; Walker, G.; Adam, J. M. Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists. Bioorg. Med. Chem. Lett. 2010, 20, 7327– 7330, DOI: 10.1016/j.bmcl.2010.10.061[Crossref], [PubMed], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVKjtb%252FP&md5=2cae1c9e1628aed9f86605a2bdc3a99bDesign, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonistsMoir, Elizabeth M.; Yoshiizumi, Kazuya; Cairns, Jim; Cowley, Phillip; Ferguson, Morag; Jeremiah, Fiona; Kiyoi, Takao; Morphy, Richard; Tierney, Jason; Wishart, Grant; York, Mark; Baker, James; Cottney, Jean E.; Houghton, Andrea K.; McPhail, Petula; Osprey, Andrew; Walker, Glenn; Adam, Julia M.Bioorganic & Medicinal Chemistry Letters (2010), 20 (24), 7327-7330CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Bicyclic piperazine derivs. were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the abs. configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compds. from metab. by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compd. I demonstrated potent antinociceptive activity in vivo.
- 161Morrison, A. J.; Adam, J. M.; Baker, J. A.; Campbell, R. A.; Clark, J. K.; Cottney, J. E.; Deehan, M.; Easson, A. M.; Fields, R.; Francis, S.; Jeremiah, F.; Keddie, N.; Kiyoi, T.; McArthur, D. R.; Meyer, K.; Ratcliffe, P. D.; Schulz, J.; Wishart, G.; Yoshiizumi, K. Design, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptor. Bioorg. Med. Chem. Lett. 2011, 21, 506– 509, DOI: 10.1016/j.bmcl.2010.10.093[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1SqsbjF&md5=5fa07b0b96427490a431477dd708d81eDesign, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptorMorrison, Angus J.; Adam, Julia M.; Baker, James A.; Campbell, Robert A.; Clark, John K.; Cottney, Jean E.; Deehan, Maureen; Easson, Anna-Marie; Fields, Ruth; Francis, Stuart; Jeremiah, Fiona; Keddie, Neil; Kiyoi, Takao; McArthur, Duncan R.; Meyer, Karsten; Ratcliffe, Paul D.; Schulz, Jurgen; Wishart, Grant; Yoshiizumi, KazuyaBioorganic & Medicinal Chemistry Letters (2011), 21 (1), 506-509CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead, a bioisostere approach replacing a piperazine amide with an azole was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of I, which had an increased duration of action in the mouse tail flick test in comparison to the lead compd.
- 162Visse, R.; Nagase, H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 2003, 92, 827– 839, DOI: 10.1161/01.RES.0000070112.80711.3D[Crossref], [PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjtFWqu7c%253D&md5=0fddee610a1b1defa7f60a14a11ae127Matrix metalloproteinases and tissue inhibitors of metalloproteinases. Structure, function, and biochemistryVisse, Robert; Nagase, HideakiCirculation Research (2003), 92 (8), 827-839CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)A review. Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biol. processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration. Currently 23 MMP genes have been identified in humans, and most are multidomain proteins. This review describes the members of the matrixin family and discusses substrate specificity, domain structure and function, the activation of proMMPs, the regulation of matrixin activity by tissue inhibitors of metalloproteinases (TIMPs), and their pathophysiol. implications.
- 163Loffek, S.; Schilling, O.; Franzke, C. W. Series “matrix metalloproteinases in lung health and disease”: biological role of matrix metalloproteinases: a critical balance. Eur. Respir. J. 2011, 38, 191– 208, DOI: 10.1183/09031936.00146510[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MnksF2ntw%253D%253D&md5=4c4fd9a00410473421a7f942afd0ce38Series "matrix metalloproteinases in lung health and disease": Biological role of matrix metalloproteinases: a critical balanceLoffek S; Schilling O; Franzke C-WThe European respiratory journal (2011), 38 (1), 191-208 ISSN:.Matrix metalloproteinases (MMPs) are members of the metzincin group of proteases which share the conserved zinc-binding motif in their catalytic active site. It was originally thought that their main function is to degrade the various components of the extracellular matrix (ECM), yet recent studies have led us to appreciate their significance as regulators of extracellular tissue signalling networks. Due to the broad spectrum of their substrate specificity, MMPs contribute to the homeostasis of many tissues and participate in several physiological processes, such as bone remodelling, angiogenesis, immunity and wound healing. MMP activity is tightly controlled at the level of transcription, pro-peptide activation and inhibition by tissue inhibitors of MMPs. Dysregulated MMP activity leads to pathological conditions such as arthritis, inflammation and cancer, thus highlighting MMPs as promising therapeutic targets. Analysis of MMP mutant mice has proved to be an essential tool for the identification of novel functions and interactions of single MMP members. Advancing our understanding of the MMP contribution to tissue homeostasis will lead us to identify causal relationships between their dysregulation and the development of disease pathologies, thus guiding us to successful MMP-directed therapies.
- 164Jackson, B. C.; Nebert, D. W.; Vasiliou, V. Update of human and mouse matrix metalloproteinase families. Hum. Genomics 2010, 4, 194– 201, DOI: 10.1186/1479-7364-4-3-194[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpt1yrurY%253D&md5=2151f04ad8848437ee2a03668ccee89eUpdate of human and mouse matrix metalloproteinase familiesJackson, Brian C.; Nebert, Daniel W.; Vasiliou, VasilisHuman Genomics (2010), 4 (3), 194-201CODEN: HGUEAT; ISSN:1479-7364. (Henry Stewart Publications)A review. Matrix metalloproteinases (MMPs) are a family of zinc proteases that degrade most of the components of the extracellular matrix (ECM). MMPs also have a no. of non-traditional roles in processing factors related to cell growth/proliferation, inflammation and more. There are 23 human MMPs and 23 mouse MMPs, most of which share orthol. among most vertebrates; other examples have been found in invertebrates and plants. MMPs are named in order of discovery, but also have been grouped by domain structure or by phylogenetic anal. MMPs are multi-domain proteins which generally contain a signal sequence; propeptide (which keeps the protein inactive until cleaved); catalytic domain; and a hemopexin-like domain (which provides substrate specificity). MMPs are thought to play a role in many disease states, including arthritis, vascular disease, lung injury, wound repair, cancer and various neurodegenerative disorders. Although there has been much clin. interest in MMP inhibitors (MMPIs), few trials have been successful - often due to the broad nature of inhibition and the complex role of different MMPs in a given disease state.
- 165Sheppard, G. S.; Florjancic, A. S.; Giesler, J. R.; Xu, L.; Guo, Y.; Davidsen, S. K.; Marcotte, P. A.; Elmore, I.; Albert, D. H.; Magoc, T. J.; Bouska, J. J.; Goodfellow, C. L.; Morgan, D. W.; Summers, J. B. Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors. Bioorg. Med. Chem. Lett. 1998, 8, 3251– 3256, DOI: 10.1016/S0960-894X(98)00597-6[Crossref], [PubMed], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXht1yn&md5=028737609bba9f565d5377c375ce530aAryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitorsSheppard, George S.; Florjancic, Alan S.; Giesler, Jamie R.; Xu, Lianhong; Guo, Yan; Davidsen, Steven K.; Marcotte, Patrick A.; Elmore, Ildiko; Albert, Daniel H.; Magoc, Terrance J.; Bouska, Jennifer J.; Goodfellow, Carole L.; Morgan, Douglas W.; Summers, James B.Bioorganic & Medicinal Chemistry Letters (1998), 8 (22), 3251-3256CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)A series of succinyl hydroxamate MMP inhibitors (I) were prepd. incorporating an aryl amino ketone moiety in place of the more typical C-terminal amino acid amides. Compds. of the C-terminal ketone series displayed potent inhibition of MMPs. Several compds. of the series were shown to be orally bioavailable.
- 166Sheppard, G. S.; Pireh, D.; Carrera, G. M., Jr.; Bures, M. G.; Heyman, H. R.; Steinman, D. H.; Davidsen, S. K.; Phillips, J. G.; Guinn, D. E.; May, P. D.; Conway, R. D.; Rhein, D. A.; Calhoun, W. C.; Albert, D. H.; Magoc, T. J.; Carter, G. W.; Summers, J. B. 3-(2-(3-Pyridinyl)thiazolidin-4-oyl)indoles, a novel series of platelet activating factor antagonists. J. Med. Chem. 1994, 37, 2011– 2032, DOI: 10.1021/jm00039a015[ACS Full Text], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmvVSmur8%253D&md5=51289cc463fdcbf18b881be8dee1c84b3-(2-(3-Pyridinyl)thiazolidin-4-oyl)indoles, a Novel Series of Platelet Activating Factor AntagonistsSheppard, George S.; Pireh, Daisy; Carrera, George M., Jr.; Bures, Mark G.; Heyman, H. Robin; Steinman, Douglas H.; Davidsen, Steven K.; Phillips, James G.; Guinn, Denise E.; et al.Journal of Medicinal Chemistry (1994), 37 (13), 2011-32CODEN: JMCMAR; ISSN:0022-2623.(2RS,4R)-3-[2-(3-Pyridinyl)thiazolidine-4-carbonyl]indoles represent a new class of potent, orally active antagonists of platelet activating factor (PAF). The compds. were prepd. by acylation of the magnesium or zinc salts of substituted indoles with (2RS,4R)-2-(3-pyridinyl)-3-(tert-butoxycarbonyl)thiazolidine-4-carbonyl chloride. The 3-acylindole moiety functions as a hydrolytically stabilized and conformationally restricted anilide replacement, which imparts a considerable boost in potency to the series. Structure-activity relationships obsd. for substitution on the indole ring system are discussed. Members of the series compare favorably with other reported PAF antagonists.
- 167Sheth, S.; Brito, R.; Mukherjea, D.; Rybak, L. P.; Ramkumar, V. Adenosine receptors: expression, function and regulation. Int. J. Mol. Sci. 2014, 15, 2024– 2052, DOI: 10.3390/ijms15022024[Crossref], [PubMed], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXptVWktrY%253D&md5=64774f90da385624fd6c27531e72e50cAdenosine receptors: expression, function and regulationSheth, Sandeep; Brito, Rafael; Mukherjea, Debashree; Rybak, Leonard P.; Ramkumar, VickramInternational Journal of Molecular Sciences (2014), 15 (2), 2024-2052, 29 pp.CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. Adenosine receptors (ARs) comprise a group of G protein-coupled receptors (GPCR) which mediate the physiol. actions of adenosine. To date, four AR subtypes have been cloned and identified in different tissues. These receptors have distinct localization, signal transduction pathways and different means of regulation upon exposure to agonists. This review will describe the biochem. characteristics and signaling cascade assocd. with each receptor and provide insight into how these receptors are regulated in response to agonists. A key property of some of these receptors is their ability to serve as sensors of cellular oxidative stress, which is transmitted by transcription factors, such as nuclear factor (NF)-κB, to regulate the expression of ARs. Recent observations of oligomerization of these receptors into homo- and hetero-dimers will be discussed. In addn., the importance of these receptors in the regulation of normal and pathol. processes such as sleep, the development of cancers and in protection against hearing loss will be examd.
- 168Carpenter, B.; Lebon, G. Human adenosine A2A receptor: molecular mechanism of ligand binding and activation. Front. Pharmacol. 2017, 8, 898, DOI: 10.3389/fphar.2017.00898[Crossref], [PubMed], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFOhurjL&md5=1190e65842b50865adca6455c318d2a3Human adenosine A2A receptor: molecular mechanism of ligand binding and activationCarpenter, Byron; Lebon, GuillaumeFrontiers in Pharmacology (2017), 8 (), 898/1-898/15CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)A review. Adenosine receptors (ARs) comprise the P1 class of purinergic receptors and belong to the largest family of integral membrane proteins in the human genome, the G protein-coupled receptors (GPCRs). ARs are classified into four subtypes, A1, A2A, A2B, and A3, which are all activated by extracellular adenosine, and play central roles in a broad range of physiol. processes, including sleep regulation, angiogenesis and modulation of the immune system. ARs are potential therapeutic targets in a variety of pathophysiol. conditions, including sleep disorders, cancer, and dementia, which has made them important targets for structural biol. Over a decade of research and innovation has culminated with the publication of more than 30 crystal structures of the human adenosine A2A receptor (A2AR), making it one of the best structurally characterized GPCRs at the at. level. In this review we analyze the structural data reported for A2AR that described for the first time the binding of mode of antagonists, including newly developed drug candidates, synthetic and endogenous agonists, sodium ions and an engineered G protein. These structures have revealed the key conformational changes induced upon agonist and G protein binding that are central to signal transduction by A2AR, and have highlighted both similarities and differences in the activation mechanism of this receptor compared to other class A GPCRs. Finally, comparison of A2AR with the recently solved structures of A1R has provided the first structural insight into the mol. determinants of ligand binding specificity in different AR subtypes.
- 169Pinna, A. Adenosine A2A receptor antagonists in Parkinson’s disease: progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs 2014, 28, 455– 474, DOI: 10.1007/s40263-014-0161-7[Crossref], [PubMed], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXosVWhtLc%253D&md5=1c12ad215ddb2384ec190027d23a3216Adenosine A2A Receptor Antagonists in Parkinson's Disease: Progress in Clinical Trials from the Newly Approved Istradefylline to Drugs in Early Development and Those Already DiscontinuedPinna, AnnalisaCNS Drugs (2014), 28 (5), 455-474CODEN: CNDREF; ISSN:1172-7047. (Springer International Publishing AG)A review. Neurotransmitters other than dopamine, such as norepinephrine, 5-hydroxytryptamine, glutamate, adenosine and acetylcholine, are involved in Parkinson's disease (PD) and contribute to its symptomatol. Thus, the progress of non-dopaminergic therapies for PD has attracted much interest in recent years. Among new classes of drugs, adenosine A2A antagonists have emerged as promising candidates. The development of new highly selective adenosine A2A receptor antagonists, and their encouraging anti-parkinsonian responses in animal models of PD, has provided a rationale for clin. trials to evaluate the therapeutic potential and the safety of these agents in patients with PD. To date, the clin. research regarding A2A antagonists and their potential utilization in PD therapy continues to evolve between drugs just or previously discontinued (preladenant and vipadenant), new derivs. in development (tozadenant, PBF-509, ST1535, ST4206 and V81444) and the relatively old drug istradefylline, which has finally been licensed as an anti-parkinsonian drug in Japan. All these compds. have been shown to have a good safety profile and be well tolerated. Moreover, results from phase II and III trials also demonstrate that A2A antagonists are effective in reducing off-time, without worsening troublesome dyskinesia, and in increasing on-time with a mild increase of non-troublesome dyskinesia, in patients at an advanced stage of PD treated with L-DOPA. In addn., early findings suggest that A2A antagonists might also be efficacious as monotherapy in patients at an early stage of PD. This review summarizes pharmacol. and clin. data available on istradefylline, tozadenant, PBF-509, ST1535, ST4206, V81444, preladenant and vipadenant.
- 170Yang, Z.; Li, X.; Ma, H.; Zheng, J.; Zhen, X.; Zhang, X. Replacement of amide with bioisosteres led to a new series of potent adenosine A2A receptor antagonists. Bioorg. Med. Chem. Lett. 2014, 24, 152– 155, DOI: 10.1016/j.bmcl.2013.11.051[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFOlsLbL&md5=68664c03d577371422198dcd578a157eReplacement of amide with bioisosteres led to a new series of potent adenosine A2A receptor antagonistsYang, Zhaohui; Li, Xuan; Ma, Haikuo; Zheng, Jiyue; Zhen, Xuechu; Zhang, XiaohuBioorganic & Medicinal Chemistry Letters (2014), 24 (1), 152-155CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The authors have previously reported a series of 2,4,6-trisubstituted pyrimidines as potent A2A receptor antagonists. The leading compds. often feature a potentially labile acetamide functional group which tends to hydrolyze under acidic conditions. Here the authors report the replacement of the acetamide functional group with bioisosteres. This effort led the authors to a new series of adenosine A2A receptor antagonists with improved potency and chem. stability.
- 171Stocchi, F.; Rascol, O.; Hauser, R. A.; Huyck, S.; Tzontcheva, A.; Capece, R.; Ho, T. W.; Sklar, P.; Lines, C.; Michelson, D.; Hewitt, D. J. Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease. Neurology 2017, 88, 2198– 2206, DOI: 10.1212/WNL.0000000000004003[Crossref], [PubMed], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1Sntbs%253D&md5=48f46e4057f7435497968585cd93dbabRandomized trial of preladenant, given as monotherapy, in patients with early Parkinson diseaseStocchi, Fabrizio; Rascol, Olivier; Hauser, Robert A.; Huyck, Susan; Tzontcheva, Anjela; Capece, Rachel; Ho, Tony W.; Sklar, Peter; Lines, Christopher; Michelson, David; Hewitt, David J.Neurology (2017), 88 (23), 2198-2206CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objective: To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy. Methods: This was a randomized, 26-wk, placebo- and active-controlled, parallel-group, multicenter, double-blind trial conducted in adults diagnosed with PD for <5 years who were not yet receiving L-dopa or dopamine agonists. Patients with a Unified Parkinson's Disease Rating Scale (UPDRS) part 3 (motor function) score ≥10 and Hoehn & Yahr score ≤3 were randomized 1:1:1:1:1 to preladenant 2, 5, or 10 mg twice daily, rasagiline 1 mg (active-control) once daily, or placebo. The primary endpoint was the change from baseline at week 26 in the sum of UPDRS parts 2 (activities of daily living) and 3 scores (UPDRS2+3). Results: The no. of patients treated was 1,007. Neither preladenant nor rasagiline was superior to placebo after 26 wk. The differences vs placebo (95% confidence interval) in UPDRS2+3 scores (with a neg. difference indicating improvement vs placebo) were preladenant 2 mg = 2.60 (0.86, 4.30), preladenant 5 mg = 1.30 (-0.41, 2.94), preladenant 10 mg = 0.40 (-1.29, 2.11), and rasagiline 1 mg = 0.30 (-1.35, 2.03). Post hoc analyses did not identify a single causal factor that could explain the finding of a failed trial. Preladenant was generally well-tolerated with few patients discontinuing due to adverse events (preladenant 7%, rasagiline 3%, placebo 4%). Conclusions: No evidence supporting the efficacy of preladenant as monotherapy was obsd. in this phase 3 trial. The lack of efficacy of the active control rasagiline makes it difficult to interpret the results. Clin. trial registration: Clinicaltrials.gov: NCT01155479. Classification of evidence: This study provides Class I evidence that for patients with early PD, preladenant is not effective as monotherapy at the doses studied (2, 5, 10 mg).
- 172Cho, J. H.; Gregersen, P. K. Genomics and the multifactorial nature of human autoimmune disease. N. Engl. J. Med. 2011, 365, 1612– 1623, DOI: 10.1056/NEJMra1100030[Crossref], [PubMed], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVSrsrbJ&md5=e3614bb47a89912b550e939eda9a91b0Genomics and the multifactorial nature of human autoimmune diseaseCho, Judy H.; Gregersen, Peter K.New England Journal of Medicine (2011), 365 (17), 1612-1623CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)A review on genomewide assocn. studies that are most robust, that most clearly implicate a disease mechanism, or that suggest a new diagnostic or therapeutic approach. For most of these disorders, genes within the major histocompatibility complex (MHC) have by far the strongest single genetic effect, and many of these assocns. have been known for decades. The new genetic findings in autoimmunity are considered in the context of the important contributions of the HLA complex to disease susceptibility and pathogenesis.
- 173Chang, Y.; Xu, S.; Ding, K. Tyrosine kinase 2 (TYK2) allosteric inhibitors to treat autoimmune diseases. J. Med. Chem. 2019, 62, 8951– 8952, DOI: 10.1021/acs.jmedchem.9b01612[ACS Full Text], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFeqtrjK&md5=d8214c7fca197889246df48f29e5c5e5Tyrosine Kinase 2 (TYK2) Allosteric Inhibitors To Treat Autoimmune DiseasesChang, Yu; Xu, Shilin; Ding, KeJournal of Medicinal Chemistry (2019), 62 (20), 8951-8952CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. TYK2 is an emerging drug target for various human autoimmune diseases. However, discovery of selective TYK2 inhibitor over other JAK family members (i.e., JAK1, 2, 3) by targeting the catalytically active site (Janus Homolog 1 (JH1) domain) is challenging. This Viewpoint discusses the discovery of a series of N-Me pyridazine-3-carboxamides as novel selective pseudokinase (JH2) domain binders of TYK2. A systematic structure-based optimization yielded a highly potent and selective allosteric TYK2 inhibitor candidate that is currently in phase III clin. trial for psoriasis.
- 174Liang, J.; Van Abbema, A.; Balazs, M.; Barrett, K.; Berezhkovsky, L.; Blair, W. S.; Chang, C.; Delarosa, D.; DeVoss, J.; Driscoll, J.; Eigenbrot, C.; Goodacre, S.; Ghilardi, N.; MacLeod, C.; Johnson, A.; Bir Kohli, P.; Lai, Y.; Lin, Z.; Mantik, P.; Menghrajani, K.; Nguyen, H.; Peng, I.; Sambrone, A.; Shia, S.; Smith, J.; Sohn, S.; Tsui, V.; Ultsch, M.; Williams, K.; Wu, L. C.; Yang, W.; Zhang, B.; Magnuson, S. Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model. Bioorg. Med. Chem. Lett. 2017, 27, 4370– 4376, DOI: 10.1016/j.bmcl.2017.08.022[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlOku7bJ&md5=d132566f504626660c52c680399c9a09Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis modelLiang, Jun; Van Abbema, Anne; Balazs, Mercedesz; Barrett, Kathy; Berezhkovsky, Leo; Blair, Wade S.; Chang, Christine; Delarosa, Donnie; De Voss, Jason; Driscoll, Jim; Eigenbrot, Charles; Goodacre, Simon; Ghilardi, Nico; MacLeod, Calum; Johnson, Adam; Bir Kohli, Pawan; Lai, Yingjie; Lin, Zhonghua; Mantik, Priscilla; Menghrajani, Kapil; Nguyen, Hieu; Peng, Ivan; Sambrone, Amy; Shia, Steven; Smith, Jan; Sohn, Sue; Tsui, Vickie; Ultsch, Mark; Williams, Karen; Wu, Lawren C.; Yang, Wenqian; Zhang, Birong; Magnuson, StevenBioorganic & Medicinal Chemistry Letters (2017), 27 (18), 4370-4376CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compd. 1. Further optimization led to generation of compd. 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compd. 30 demonstrated dose-dependent redn. of IL-17 prodn. in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a redn. of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.
- 175Baures, P. W.; Ojala, W. H.; Costain, W. J.; Ott, M. C.; Pradhan, A.; Gleason, W. B.; Mishra, R. K.; Johnson, R. L. Design, synthesis, and dopamine receptor modulating activity of diketopiperazine peptidomimetics of L-prolyl-L-leucylglycinamide. J. Med. Chem. 1997, 40, 3594– 3600, DOI: 10.1021/jm970328b[ACS Full Text], [CAS], Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmtlyntLs%253D&md5=157d4fe28293903d9b01891afd50e3f2Design, Synthesis, and Dopamine Receptor-Modulating Activity of Diketopiperazine Peptidomimetics of L-Prolyl-L-leucylglycinamideBaures, Paul W.; Ojala, William H.; Costain, Willard J.; Ott, Michael C.; Gleason, William B.; Mishra, Ram K.; Johnson, Rodney L.Journal of Medicinal Chemistry (1997), 40 (22), 3594-3600CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The diketopiperazine "C5" conformational mimic has been incorporated into the L-prolyl-L-leucylglycinamide (PLG; I) structure and into the bicyclic lactam I-peptidomimetic structure II to give III and IV, resp. These analogs were designed to explore the idea that the N-terminal "C5" conformation, which was found in the crystal structure of V and which was mimicked in VI by the diketopiperazine function, was a factor in the high potency of these two agents. Through the use of the [3H]spiroperidol/N-propylnorapomorphine (NPA) D2 receptor competitive binding assay, both III and IV were found to increase the affinity of the dopamine receptor for agonists and both were found to increase the percentage of D2 receptors which existed in the high-affinity state. These effects were obsd. when Gpp(NH)p was either absent or present, and they were analogous to the effects obsd. previously for I and the I-peptidomimetics V and VI. However, the potency seen with III and IV was less than that seen for V and VI, suggesting that while the N-terminal "C5" conformation may play a role in the potency of the γ-lactam peptidomimetics of I, it does not appear to be the primary factor. In the 6-hydroxydopamine-lesioned animal model of Parkinson's disease, III altered apomorphine-induced rotational behavior in a dose-dependent manner. The max. effect occurred at a dose of 0.01 mg/kg i.p. and resulted in a 52.27 ± 13.96% (p < 0.001, n = 7) increase in rotations compared to apomorphine administered alone.
- 176Chiu, S.; Paulose, C. S.; Mishra, R. K. Effect of L-prolyl-L-leucyl-glycinamide (PLG) on neuroleptic-induced catalepsy and dopamine/neuroleptic receptor bindings. Peptides 1981, 2, 105– 111, DOI: 10.1016/S0196-9781(81)80019-8[Crossref], [PubMed], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXhs1yntbk%253D&md5=bb5761c2f994899475efdbee3d344c93Effect of L-prolyl-L-leucylglycinamide (PLG) on neuroleptic-induced catalepsy and dopamine/neuroleptic receptor bindingsChiu, Simon; Paulose, C. S.; Mishra, Ram K.Peptides (New York, NY, United States) (1981), 2 (1), 105-11CODEN: PPTDD5; ISSN:0196-9781.The mechanism of action subserving the potential antiParkinsonian properties of L-prolyl-L-leucyl-glycinamide (PLG) [2002-44-0] was investigated in behavioral and neurochem. models of dopaminergic function in the rat. Acute administration of PLG (20 and 40 mg/kg s.c.) failed to alter appreciably the intensity of the cateleptic response elicited by haloperidol [52-86-8] (3 mg/kg i.p.). By contrast, chronic PLG treatment (20, 40 and 80 mg/kg s.c.-twice daily for 5 days) significantly attenuated haloperidol-induced catalepsy. The effect of PLG on in vitro dopamine/neuroleptic receptor binding in rat striatum as differently labeled by apomorphine [58-00-4] and spiroperidol was also examd. PLG selectively enhanced the affinity of the sp. binding of agonist [3H]apomorphine to dopamine receptors in the striatum, but had no effect on 3H labeled spiroperidol [749-02-0] binding. Apparently, PLG may facilitate nigro-striatal dopaminergic neurotransmission through interacting with a unique PLG receptor functionally coupled to the dopamine receptor-adenylate cyclase complex.
- 177Srivastava, L. K.; Bajwa, S. B.; Johnson, R. L.; Mishra, R. K. Interaction of L-prolyl-L-leucyl glycinamide with dopamine D2 receptor: evidence for modulation of agonist affinity states in bovine striatal membranes. J. Neurochem. 1988, 50, 960– 968, DOI: 10.1111/j.1471-4159.1988.tb03005.x[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXht1Gjurs%253D&md5=cb868b612e75938ae1a317938f949cbaInteraction of L-prolyl-L-leucyl glycinamide with dopamine D2 receptor: evidence for modulation of agonist affinity states in bovine striatal membranesSrivastava, Lalit K.; Bajwa, Samina B.; Johnson, Rodney L.; Mishra, Ram K.Journal of Neurochemistry (1988), 50 (3), 960-8CODEN: JONRA9; ISSN:0022-3042.The role of the hypothalamic tripeptide L-prolyl-L-leucyl-glycinamide (PLG) in modulating the agonist binding to bovine striatal dopamine D2 receptor was investigated using a selective high-affinity agonist, propylnorapomorphine (NPA). PLG caused an enhancement in [3H]NPA binding in striatal membranes in a dose-dependent manner, the max. effect being obsd. at 10-7-10-6M PLG. The Scatchard anal. of [3H]NPA binding to membranes preincubated with 10-6M PLG revealed an increase in the affinity of the agonist binding sites. In contrast, there was no effect of PLG on the binding pattern of the antagonist [3H]spiroperidol. The antagonist vs. agonist competition curves analyzed for agonist high- and low-affinity states of the receptor displayed an increase in the population and affinity of the high-affinity form of the receptor with PLG treatment. The low-affinity sites concomitantly decreased with relatively small change in the affinity for the agonists. Almost similar results were obtained when either NPA or apomorphine was used in the competition expts. A partial antagonistic effect of PLG on Gpp(NH)p-induced inhibition of high-affinity agonist binding was also obsd., as the ratio of high- to low-affinity forms of the receptor was higher in the PLG-treated membranes compared to the controls. Direct [3H]NPA binding expts. demonstrated that PLG attenuated the Gpp(NH)p-induced inhibition of agonist binding by increasing the EC50 of the nucleotide (concn. that inhibits 50% of the specific binding). No effect of PLG on high-affinity [3H]NPA binding, however, was obsd. when the striatal membranes were preincubated with Gpp(NH)p. The binding of antagonists and agonists to α2 adrenergic receptors, neg. coupled to adenylate cyclase in the striatum, was not affected by PLG. Apparently, PLG modulates the affinity states of the dopamine D2 receptor, possibly by enhancing its interaction with the guanine nucleotide regulatory protein.
- 178Baures, P. W.; Ojala, W. H.; Gleason, W. B.; Mishra, R. K.; Johnson, R. L. Design, synthesis, X-ray analysis, and dopamine receptor-modulating activity of mimics of the ″C5″ hydrogen-bonded conformation in the peptidomimetic 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1-pyrrolidineacetamide. J. Med. Chem. 1994, 37, 3677– 3683, DOI: 10.1021/jm00048a003[ACS Full Text], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmtlWgt70%253D&md5=c45c17c74ce4c1da86e61d7698dbb330Design, Synthesis, X-ray Analysis, and Dopamine Receptor-Modulating Activity of Mimics of the "C5" Hydrogen-Bonded Conformation in the Peptidomimetic 2-Oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1-pyrrolidineacetamideBaures, Paul W.; Ojala, William H.; Gleason, William B.; Mishra, Ram K.; Johnson, Rodney L.Journal of Medicinal Chemistry (1994), 37 (22), 3677-83CODEN: JMCMAR; ISSN:0022-2623.Analogs I and II (R = NH2) were designed and prepd. as mimics of the "C5" hydrogen-bonded structure found in the crystal structure of the title compd (III). Both compds. effectively restrict the ψ1 torsional angle to very near the value found in the x-ray structure of III, as seen in the x-ray crystallog. detn. of I ester analog II (R = OMe). I and II (R = NH2) were tested for their ability to enhance the binding of the dopamine D2 receptor agonist N-propylnorapomorphine (NPA) in the absence and presence of 5'-guanylylimidodiphosphate (Gpp(NH)p). Both compds. enhanced [3H]NPA binding in a dose-dependent manner by increasing both the binding affinity of the agonist and the no. of high-affinity sites available for binding. Both I and II (R = NH2) also attenuated the Gpp(NH)p-induced conversion of D2 receptor high-affinity states to the low-affinity states.
- 179Yu, K. L.; Rajakumar, G.; Srivastava, L. K.; Mishra, R. K.; Johnson, R. L. Dopamine receptor modulation by conformationally constrained analogues of Pro-Leu-Gly-NH2. J. Med. Chem. 1988, 31, 1430– 1436, DOI: 10.1021/jm00402a031[ACS Full Text], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXkt1egtb8%253D&md5=4b5fb96c48f174cf60d92f4ab56aace8Dopamine receptor modulation by conformationally constrained analogs of Pro-Leu-Gly-NH2Yu, Kuo Long; Rajakumar, G.; Srivastava, Lalit K.; Mishra, Ram K.; Johnson, Rodney L.Journal of Medicinal Chemistry (1988), 31 (7), 1430-6CODEN: JMCMAR; ISSN:0022-2623.Two series of conformationally constrained analogs of Pro-Leu-Gly-NH2 (PLG) have been synthesized. In one series, the Leu-Gly-NH2 dipeptide segment of PLG was replaced with the γ-lactam residues (S)- and (R)-3-amino-2-oxopyrrolidineacetamide and the δ-lactam residue (S)-3-amino-2-oxopiperidineacetamide. The corresponding δ-lactam analogs of pyroGlu-Leu-Gly-NH2 were also synthesized. In a second series of analogs, the glycinamide residue of PLG was replaced with the 2-ketopiperazine, (S)-3-amino-2-pyrrolidone, and (S)-3-amino-2-piperidone residues. The above analogs were tested for their ability to enhance the binding of the dopamine receptor agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) to striatal dopamine receptors. Only the γ-lactam analog I possess significant activity. This analog was 10,000 times more active than PLG, under preincubation conditions. It significantly enhanced the binding of ADTN at concns. of 10-9 and 10-10 M.
- 180Mishra, R. K.; Srivastava, L. K.; Johnson, R. L. Modulation of high-affinity CNS dopamine D2 receptor by L-pro-L-leu-glycinamide (PLG) analogue 3(R)-(N-L-prolylamino)-2-oxo-1-pyrrolidineacetamide. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1990, 14, 821– 827, DOI: 10.1016/0278-5846(90)90054-K[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXkt1amu74%253D&md5=4c2d99c4e75972bc622039b76307e4ccModulation of high-affinity CNS dopamine D2 receptor by L-Pro-L-Leu-glycinamide (PLG) analog 3(R)-(N-L-prolylamino)-2-oxo-1-pyrrolidineacetamideMishra, Ram K.; Srivastava, Lalit K.; Johnson, R. L.Progress in Neuro-Psychopharmacology & Biological Psychiatry (1990), 14 (5), 821-7CODEN: PNPPD7; ISSN:0278-5846.In previous studies, one of the conformationally constrained analogs of PLG, 3(R)-(N-L-prolylamino)-2-oxo-1-pyrrolidineacetamide (PAOPA), was extremely potent in enhancing the [3H]ADTN binding when membranes were preincubated with this compd. PAOPA was without effect when directly added to assay tubes. In the present study, the effect of PAOPA was examd. on agonist binding to the high-affinity state of the dopamine D2 receptor. PAOPA was able to prevent the GTP-induced conversion of the high-affinity state of dopamine D2 receptor to the low-affinity state. Thus, PAOPA modulates the affinity states of the dopamine D2 receptor, possibly by affecting its interaction with the G-protein(s).
- 181Subasinghe, N. L.; Bontems, R. J.; McIntee, E.; Mishra, R. K.; Johnson, R. L. Bicyclic thiazolidine lactam peptidomimetics of the dopamine receptor modulating peptide Pro-Leu-Gly-NH2. J. Med. Chem. 1993, 36, 2356– 2361, DOI: 10.1021/jm00068a013[ACS Full Text], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXlvFGnuro%253D&md5=3a777e873523f6b98ac8ba31951ffc0aBicyclic thiazolidine lactam peptidomimetics of the dopamine receptor modulating peptide Pro-Leu-Gly-NH2Subasinghe, Nalin L.; Bontems, Roger J.; McIntee, Edward; Mishra, Ram K.; Johnson, Rodney L.Journal of Medicinal Chemistry (1993), 36 (16), 2356-61CODEN: JMCMAR; ISSN:0022-2623.Bicyclic thiazolidine lactam peptidomimetics (I-III) were synthesized as potential analogs of the dopamine receptor modulating peptide Pro-Leu-Gly-NH2 (PLG). I and II were designed to constrain 2, ψ2 and φ3, of the 4 torsion angles that define a β-turn to values approximating those found for a type-II β-turn, while III was designed as a compd. that could not achieve a β-turn conformation. I and II enhanced the binding of the dopamine receptor agonist ADTN to the dopamine receptor, while III was inactive. Like PLG, the dose-response curves for I and II were bell-shaped in nature with the max. effect occurring at a concn. of 1 μM. I and II were more effective than PLG in enhancing the binding of ADTN to dopamine receptors. I enhanced the binding of ADTN by almost 200%, while II enhanced the binding of ADTN by about 75%. These results provide further evidence in support of the hypothesis that the bioactive conformation of PLG is a type-II β-turn.
- 182Borthwick, A. D. 2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products. Chem. Rev. 2012, 112, 3641– 3716, DOI: 10.1021/cr200398y[ACS Full Text], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmvV2ns78%253D&md5=2c30d3c51f862e424679b65784f03aa62,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural ProductsBorthwick, Alan D.Chemical Reviews (Washington, DC, United States) (2012), 112 (7), 3641-3716CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. 2,5-Diketopiperazines [such as cyclo(Trp-Pro), cyclo(Trp-Trp) and cyclo(Pro-Pro), etc.] are cyclic dipeptides obtained by the condensation of two α-amino acids. They are not only abound in nature, but also, are often produced as degrdn. products of polypeptides, esp., in processed food and beverages. The objective of the present review is to comprehensively cover the literature from 1993 until the end of 2010 on the structure, reactions, medicinal chem., and potential therapeutic applications of 2,5-diketopiperazines, in particular natural products that exhibit biol. activity. This review focuses on the soln.-phase synthesis of 2,5-diketopiperazines from the past decade (2000-2010) and will only touch briefly on solid-phase synthesis.
- 183Verma, K.; Zang, T.; Penning, T. M.; Trippier, P. C. Potent and highly selective aldo-keto reductase 1C3 (AKR1C3) inhibitors act as chemotherapeutic potentiators in acute myeloid leukemia and T-Cell acute lymphoblastic leukemia. J. Med. Chem. 2019, 62, 3590– 3616, DOI: 10.1021/acs.jmedchem.9b00090[ACS Full Text], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkt1Wgtrw%253D&md5=7142848109b6a6f7197549fd07e3057bPotent and Highly Selective Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors Act as Chemotherapeutic Potentiators in Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic LeukemiaVerma, Kshitij; Zang, Tianzhu; Penning, Trevor M.; Trippier, Paul C.Journal of Medicinal Chemistry (2019), 62 (7), 3590-3616CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Aldo-keto reductase 1C3 (AKR1C3) catalyzes the synthesis of 9α,11β-prostaglandin (PG) F2α and PGF2α prostanoids that sustain the growth of myeloid precursors in the bone marrow. The enzyme is overexpressed in acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL). Moreover, AKR1C3 confers chemotherapeutic resistance to the anthracyclines; first-line agents for the treatment of leukemias. The highly homologous isoforms AKR1C1 and AKR1C2 inactive 5α-dihydroprogesterone and their inhibition would be undesirable. We report herein, the identification of AKR1C3 inhibitors that demonstrate exquisite isoform selectivity for AKR1C3 over the other closely related isoforms to the order of >2800-fold. Biol. evaluation of our isoform selective inhibitors revealed a high degree of synergistic drug action in combination with the clin. leukemia therapeutics daunorubicin and cytarabine in in vitro cellular models of AML and primary patient-derived T-ALL cells. Our developed compds. exhibited >100-fold dose redn. index that results in complete resensitization of a daunorubicin-resistant AML cell line to the chemotherapeutic and >100-fold dose redn. of cytarabine in both AML cell lines and primary T-ALL cells.
- 184de la Fuente Revenga, M.; Fernandez-Saez, N.; Herrera-Arozamena, C.; Morales-Garcia, J. A.; Alonso-Gil, S.; Perez-Castillo, A.; Caignard, D. H.; Rivara, S.; Rodriguez-Franco, M. I. Novel N-acetyl bioisosteres of melatonin: melatonergic receptor pharmacology, physicochemical studies, and phenotypic assessment of their neurogenic potential. J. Med. Chem. 2015, 58, 4998– 5014, DOI: 10.1021/acs.jmedchem.5b00245[ACS Full Text], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptFajsL0%253D&md5=0866e59c6e177e9e2a89660f5a4c6cddNovel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potentialde la Fuente Revenga, Mario; Fernandez-Saez, Nerea; Herrera-Arozamena, Clara; Morales-Garcia, Jose A.; Alonso-Gil, Sandra; Perez-Castillo, Ana; Caignard, Daniel-Henri; Rivara, Silvia; Rodriguez-Franco, Maria IsabelJournal of Medicinal Chemistry (2015), 58 (12), 4998-5014CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Herein the authors present a new family of melatonin-based compds., in which the acetamido group of melatonin has been bioisosterically replaced by a series of reversed amides and azoles, such as oxazole, 1,2,4-oxadiazole, and 1,3,4-oxadiazole, as well as other related five-membered heterocycles, namely, 1,3,4-oxadiazol(thio)ones, 1,3,4-triazol(thio)ones, and an 1,3,4-thiadiazole. New compds. were fully characterized at melatonin receptors (MT1R and MT2R), and results were rationalized by superimposition studies of their structures to the bioactive conformation of melatonin. The authors also found that several of these melatonin-based compds. promoted differentiation of rat neural stem cells to a neuronal phenotype in vitro, in some cases to a higher extent than melatonin. This unique profile constitutes the starting point for further pharmacol. studies to assess the mechanistic pathways and the relevance of neurogenesis induced by melatonin-related structures.
- 185Byrns, M. C.; Penning, T. M. Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogs. Chem.-Biol. Interact. 2009, 178, 221– 227, DOI: 10.1016/j.cbi.2008.10.024[Crossref], [PubMed], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFOjtb0%253D&md5=67a4ebbb87d66f87b96e8b85cfd06a08Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): Role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogsByrns, Michael C.; Penning, Trevor M.Chemico-Biological Interactions (2009), 178 (1-3), 221-227CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)Aldo-keto reductase (AKR) 1C3 catalyzes the NADPH-dependent redn. of Δ4-androstene-3,17-dione to yield testosterone, redn. of estrone to yield 17β-estradiol and redn. of progesterone to yield 20α-hydroxyprogesterone. In addn., it functions as a prostaglandin (PG) F synthase and reduces PGH2 to PGF2α and PGD2 to 11β-PGF2. Immunohistochem. showed that AKR1C3 is over-expressed in invasive ductal carcinoma of the breast. Retroviral expression of AKR1C3 in MCF-7 breast carcinoma cells shows that each of the assigned reactions occur in a breast cell microenvironment. Steroid and prostaglandin conversions were monitored by radiochromatog. Prostaglandin conversion was validated by a 2nd method using HPLC coupled to APCI-MRM/MS. The combined effect of the AKR1C3 catalyzed 17- and 20-ketosteroid redns. will be to increase the 17β-estradiol:progesterone ratio in the breast. In addn., formation of PGF2 epimers would activate F prostanoid receptors and deprive PPARγ of its putative anti-proliferative PGJ2 ligands. Thus, AKR1C3 is a source of proliferative signals and a potential therapeutic target for hormone-dependent and -independent breast cancer. Two strategies for AKR1C3 inhibition based on non-steroidal anti-inflammatory drugs were developed. The 1st strategy uses the Ullmann coupling reaction to generate N-phenylanthranilate derivs. that inhibit AKR1C enzymes without affecting PGH2 synthase (PGHS) 1 or PGHS-2. The second strategy exploits the selective inhibition of AKR1C3 by indomethacin, which did not inhibit highly related AKR1C1 or AKR1C2. Using known structure-activity relationships for the inhibition of PGHS-1 and PGHS-2 by indole acetic acids we obtained N-(4-chlorobenzoyl)-melatonin as a specific AKR1C3 inhibitor (K I = 6.0 μM) that does not inhibit PGHS-1, PGHS-2, AKR1C1, or AKR1C2. Both strategies are informed by crystal structures of ternary AKR1C3·NADP+·NSAID complexes. The identification of NSAID analogs as specific inhibitors of AKR1C3 will help validate its role in the proliferation of breast cancer cells.
- 186Ji, Q.; Chang, L.; Stanczyk, F. Z.; Ookhtens, M.; Sherrod, A.; Stolz, A. Impaired dihydrotestosterone catabolism in human prostate cancer: critical role of AKR1C2 as a pre-receptor regulator of androgen receptor signaling. Cancer Res. 2007, 67, 1361– 1369, DOI: 10.1158/0008-5472.CAN-06-1593[Crossref], [PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1ynt7w%253D&md5=5a85f84c8edadd0b3e10dc913484652fImpaired Dihydrotestosterone Catabolism in Human Prostate Cancer: Critical Role of AKR1C2 as a Pre-Receptor Regulator of Androgen Receptor SignalingJi, Qing; Chang, Lilly; Stanczyk, Frank Z.; Ookhtens, Murad; Sherrod, Andy; Stolz, AndrewCancer Research (2007), 67 (3), 1361-1369CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)We previously reported the selective loss of AKR1C2 and AKR1C1 in prostate cancers compared with their expression in paired benign tissues. We now report that dihydrotestosterone (DHT) levels are significantly greater in prostate cancer tumors compared with their paired benign tissues. Decreased catabolism seems to account for the increased DHT levels as expression of AKR1C2 and SRD5A2 was reduced in these tumors compared with their paired benign tissues. After 4 h of incubation with benign tissue samples, 3H-DHT was predominately catabolized to the 5α-androstane-3α,17beta-diol metabolite. Reduced capacity to metabolize DHT was obsd. in tumor samples from four of five freshly isolated pairs of tissue samples, which paralleled loss of AKR1C2 and AKR1C1 expression. LAPC-4 cells transiently transfected with AKR1C1 and AKR1C2, but not AKR1C3, were able to significantly inhibit a dose-dependent, DHT-stimulated proliferation, which was assocd. with a significant redn. in the concn. of DHT remaining in the media. R1881-stimulated proliferation was equiv. in all transfected cells, showing that metab. of DHT was responsible for the inhibition of proliferation. PC-3 cells overexpressing AKR1C2 and, to a lesser extent, AKR1C1 were able to significantly inhibit DHT-dependent androgen receptor reporter activity, which was abrogated by increasing DHT levels. We speculate that selective loss of AKR1C2 in prostate cancer promotes clonal expansion of tumor cells by enhancement of androgen-dependent cellular proliferation by reducing DHT metab.
- 187Penning, T. M.; Bauman, D. R.; Jin, Y.; Rizner, T. L. Identification of the molecular switch that regulates access of 5α-DHT to the androgen receptor. Mol. Cell. Endocrinol. 2007, 265–266, 77– 82, DOI: 10.1016/j.mce.2006.12.007[Crossref], [PubMed], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXit12msb0%253D&md5=2ff342e0a26d247c4e901431f0f8ba2bIdentification of the molecular switch that regulates access of 5α-DHT to the androgen receptorPenning, Trevor M.; Bauman, David R.; Jin, Yi; Rizner, Tea LanisikMolecular and Cellular Endocrinology (2007), 265-266 (), 77-82CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ltd.)A review. Pairs of hydroxysteroid dehydrogenases (HSDs) govern ligand access to steroid receptors in target tissues and act as mol. switches. By acting as reductases or oxidases, HSDs convert potent ligands into their cognate inactive metabolites or vice versa. This pre-receptor regulation of steroid hormone action may have profound effects on hormonal response. We have identified the HSDs responsible for regulating ligand access to the androgen receptor (AR) in human prostate. Type 3 3α-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) acts solely as a reductase to convert 5α-dihydrotestosterone (DHT), a potent ligand for the AR (Kd=10-11 M for the AR), to the inactive androgen 3α-androstanediol (Kd=10-6 M for the AR); while RoDH like 3α-HSD (a short-chain dehydrogenase/reductase (SDR)) acts solely as an oxidase to convert 3α-androstanediol back to 5α-DHT. Our studies suggest that aldo-keto reductase (AKRs) and SDRs function as reductases and oxidases, resp., to control ligand access to nuclear receptors.
- 188Yin, Y. D.; Fu, M.; Brooke, D. G.; Heinrich, D. M.; Denny, W. A.; Jamieson, S. M. The activity of SN33638, an inhibitor of AKR1C3, on testosterone and 17β-estradiol production and function in castration-resistant prostate cancer and ER-positive breast cancer. Front. Oncol. 2014, 4, 159, DOI: 10.3389/fonc.2014.00159[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfptVKksw%253D%253D&md5=ef337064d6f2a20aa22ac29867ff6b13The Activity of SN33638, an Inhibitor of AKR1C3, on Testosterone and 17β-Estradiol Production and Function in Castration-Resistant Prostate Cancer and ER-Positive Breast CancerYin Yarong Diana; Fu Melissa; Brooke Darby G; Heinrich Daniel M; Denny William A; Jamieson Stephen M FFrontiers in oncology (2014), 4 (), 159 ISSN:2234-943X.AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC) and estrogen receptor (ER)-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression. A panel of CRPC, ER-positive breast cancer and high/low AKR1C3-expressing cell lines were treated with SN33638, a selective inhibitor of AKR1C3, in the presence of hormone or prostaglandin (PG) precursors, prior to evaluation of cell proliferation and levels of 11β-PG F2α (11β-PGF2α), testosterone, 17β-estradiol, and prostate-specific antigen (PSA). A meta-analysis of AKR1C3 mRNA expression in patient samples was also conducted, which revealed that AKR1C3 mRNA was upregulated in CRPC, but downregulated in ER-positive breast cancer. 11β-PGF2α and testosterone levels in the cell line panel correlated with AKR1C3 protein expression. SN33638 prevented 11β-PGF2α formation in cell lines that expressed AKR1C3, but partially inhibited testosterone formation and subsequently cell proliferation and/or PSA expression only in high (LAPC4 AKR1C3-overexpressing cells) or moderate (22RV1) AKR1C3-expressing cell lines. SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines. Although SN33638 could prevent 11β-PGF2α formation, its ability to prevent testosterone and 17β-estradiol production and their roles in CRPC and ER-positive breast cancer progression was limited due to AKR1C3-independent steroid hormone production, except in LAPC4 AKR1C3 cells where the majority of testosterone was AKR1C3-dependent. These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required for their growth.
- 189Loriot, Y.; Fizazi, K.; Jones, R. J.; Van den Brande, J.; Molife, R. L.; Omlin, A.; James, N. D.; Baskin-Bey, E.; Heeringa, M.; Baron, B.; Holtkamp, G. M.; Ouatas, T.; De Bono, J. S. Safety, tolerability and anti-tumour activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer: multi-centre phase I/II study. Invest. New Drugs 2014, 32, 995– 1004, DOI: 10.1007/s10637-014-0101-x[Crossref], [PubMed], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXntlejs7g%253D&md5=58d51588f7b4984b516a4c4a410189e3Safety, tolerability and anti-tumor activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer: multi-centre phase I/II studyLoriot, Yohann; Fizazi, Karim; Jones, Robert J.; Van den Brande, Jan; Molife, Rhoda L.; Omlin, Aurelius; James, Nicholas D.; Baskin-Bey, Edwina; Heeringa, Marten; Baron, Benoit; Holtkamp, Gertjan M.; Ouatas, Taoufik; De Bono, Johann S.Investigational New Drugs (2014), 32 (5), 995-1004CODEN: INNDDK; ISSN:0167-6997. (Springer)Background: ASP9521 is a first-in-class orally available inhibitor of the enzyme 17 β-hydroxysteroid dehydrogenase type 5 (17 βHSD5; AKR1C3), catalyzing the conversion of dehydroepiandrosterone and androstenedione into 5-androstenediol and testosterone. It has demonstrated anti-tumor activity in in vitro and in vivo preclin. models. Material and methods: This first-in-man phase I/II study utilized a 3 + 3 dose escalation design starting at 30 mg ASP9521/day, with the aim of defining a max. tolerated dose, as defined by the incidence of dose-limiting toxicities. Eligible patients received ASP9521 orally for 12 wk. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics and anti-tumor activity were assessed. Results: Thirteen patients (median age: 68 years; range 52-76) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy were included; 12 patients discontinued treatment at or before week 13, mainly due to disease progression. The most common adverse events were grade 1/2 and included asthenia (N = 5), constipation (N = 4), diarrhoea (N = 3), back pain (N = 3) and cancer pain (N = 3). PK demonstrated a half-life (t1/2) ranging from 16 to 35 h, rapid absorption and dose proportionality. No biochem. or radiol. responses were identified; neither endocrine biomarker levels nor circulating tumor cell counts were altered by ASP9521. Given the lack of observable clin. activity, the study was terminated without implementing a planned 12-wk dose expansion part at selected doses or a planned food-effect study part. Conclusions: In patients with mCRPC, ASP9521 demonstrated dose-proportional increase in exposure over the doses evaluated, with an acceptable safety and tolerability profile. However, the novel androgen biosynthesis inhibitor showed no relevant evidence of clin. activity.
- 190Kikuchi, A.; Furutani, T.; Azami, H.; Watanabe, K.; Niimi, T.; Kamiyama, Y.; Kuromitsu, S.; Baskin-Bey, E.; Heeringa, M.; Ouatas, T.; Enjo, K. In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3). Invest. New Drugs 2014, 32, 860– 870, DOI: 10.1007/s10637-014-0130-5[Crossref], [PubMed], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFWisrfL&md5=2aeb865497f4e85ba52d7556da8fab22In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3)Kikuchi, Aya; Furutani, Takashi; Azami, Hidenori; Watanabe, Kazushi; Niimi, Tatsuya; Kamiyama, Yoshiteru; Kuromitsu, Sadao; Baskin-Bey, Edwina; Heeringa, Marten; Ouatas, Taoufik; Enjo, KentaroInvestigational New Drugs (2014), 32 (5), 860-870CODEN: INNDDK; ISSN:0167-6997. (Springer)Background Aldo-keto reductase 1C3 [AKR1C3;17β-hydroxysteroid dehydrogenase type 5 (17βHSD5)], plays a crucial role in persistent prodn. of androgens despite castration, by catalyzing conversion of the adrenal androgens dehydroepiandrosterone and androstenedione (AD) into androstenediol and testosterone (T). Hence, AKR1C3 is a promising therapeutic target in castration-resistant prostate cancer, as combination of an AKR1C3 inhibitor and a gonadotropin-releasing hormone analog may lead to complete androgen blockade. This study describes the preclin. characterization of the novel AKR1C3 inhibitor ASP9521. Methods The inhibitory effect of ASP9521 on AKR1C3-mediated conversion from AD into T was evaluated both in vitro and in vivo, using CWR22R xenografted mice. The effect of ASP9521 on PSA prodn. and cell proliferation was tested using LNCaP cells stably expressing human AKR1C3 (LNCaP-AKR1C3). Pharmacokinetics of ASP9521 were studied in rats, dogs and cynomolgus monkeys. Results ASP9521 inhibited conversion of AD into T by recombinant human or cynomolgus monkey AKR1C3 in a concn.-dependent manner (IC50,human: 11 nmol/L; IC50,monkey: 49 nmol/L). ASP9521 showed >100-fold selectivity for AKR1C3 over the isoform AKR1C2. In LNCaP-AKR1C3 cells, ASP9521 suppressed AD-dependent PSA prodn. and cell proliferation. In CWR22R xenografts, single oral administration of ASP9521 (3 mg/kg) inhibited AD-induced intratumoral T prodn. and this inhibitory effect was maintained for 24 h. After oral administration, ASP9521 was rapidly eliminated from plasma, while its intratumoral concn. remained high. The bioavailability of ASP9521 after oral administration (1 mg/kg) was 35 %, 78 % and 58 % in rats, dogs and monkeys, resp. Conclusions ASP9521 is a potent, selective, orally bioavailable AKR1C3 inhibitor.
- 191Endo, S.; Matsunaga, T.; Kanamori, A.; Otsuji, Y.; Nagai, H.; Sundaram, K.; El-Kabbani, O.; Toyooka, N.; Ohta, S.; Hara, A. Selective inhibition of human type-5 17β-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis. J. Nat. Prod. 2012, 75, 716– 721, DOI: 10.1021/np201002x[ACS Full Text], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlsFKlt7g%253D&md5=d3b7ad46dceac38f43b372284336f1dcSelective Inhibition of Human Type-5 17β-Hydroxysteroid Dehydrogenase (AKR1C3) by Baccharin, a Component of Brazilian PropolisEndo, Satoshi; Matsunaga, Toshiyuki; Kanamori, Ayano; Otsuji, Yoko; Nagai, Hiroko; Sundaram, Krithika; El-Kabbani, Ossama; Toyooka, Naoki; Ohta, Shozo; Hara, AkiraJournal of Natural Products (2012), 75 (4), 716-721CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)The human aldo-keto reductase (AKR) 1C3, also known as type-5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase, has been suggested as a therapeutic target in the treatment of prostate and breast cancers. In this study, AKR1C3 inhibition was examd. by Brazilian propolis-derived cinnamic acid derivs. that show potential antitumor activity, and baccharin is a potent competitive inhibitor (Ki 56 nM) with high selectivity, showing no significant inhibition toward other AKR1C isoforms (AKR1C1, AKR1C2, and AKR1C4). Mol. docking and site-directed mutagenesis studies suggested that the nonconserved residues Ser 118, Met 120, and Phe 311 in AKR1C3 are important for detg. the inhibitory potency and selectivity of baccharin. The AKR1C3-mediated metab. of 17-ketosteroid and farnesal in cancer cells was inhibited by baccharin, which was effective from 0.2 μM with an IC50 value of about 30 μM. Addnl., baccharin suppressed the proliferation of PC3 prostatic cancer cells stimulated by AKR1C3 overexpression. This study is the first demonstration that baccharin is a highly selective inhibitor of AKR1C3.
- 192Zang, T.; Verma, K.; Chen, M.; Jin, Y.; Trippier, P. C.; Penning, T. M. Screening baccharin analogs as selective inhibitors against type 5 17β-hydroxysteroid dehydrogenase (AKR1C3). Chem.-Biol. Interact. 2015, 234, 339– 348, DOI: 10.1016/j.cbi.2014.12.015[Crossref], [PubMed], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXkslejsw%253D%253D&md5=13166382f86d745545f3c5dc55077cd8Screening baccharin analogs as selective inhibitors against type 5 17β-hydroxysteroid dehydrogenase (AKR1C3)Zang, Tianzhu; Verma, Kshitij; Chen, Mo; Jin, Yi; Trippier, Paul C.; Penning, Trevor M.Chemico-Biological Interactions (2015), 234 (), 339-348CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase, is a downstream steroidogenic enzyme and converts androgen precursors to the potent androgen receptor ligands: testosterone and 5α-dihydrotestosterone. Studies have shown that AKR1C3 is involved in the development of castration resistant prostate cancer (CRPC) and that it is a rational drug target for the treatment of CRPC. Baccharin, a component of Brazilian propolis, has been obsd. to exhibit a high inhibitory potency and selectivity for AKR1C3 over other AKR1C isoforms and is a promising lead compd. for developing more potent and selective inhibitors. Here, we report the screening of fifteen baccharin analogs as selective inhibitors against AKR1C3 vs. AKR1C2 (type 3 3α-hydroxysteroid dehydrogenase). Among these analogs, the inhibitory activity and selectivity of thirteen compds. were evaluated for the first time. The substitution of the 4-dihydrocinnamoyloxy group of baccharin by an acetate group displayed nanomolar inhibitory potency (IC50: 440 nM) and a 102-fold selectivity over AKR1C2. By contrast, when the cinnamic acid group of baccharin was esterified, there was a dramatic decrease in potency and selectivity for AKR1C3 in comparison to baccharin. Low or sub-micromolar inhibition was obsd. when the 3-prenyl group of baccharin was removed, and the selectivity over AKR1C2 was low. Although unsubstituted baccharin was still the most potent (IC50: 100 nM) and selective inhibitor for AKR1C3, these data provide structure-activity relationships required for the optimization of new baccharin analogs. They suggest that the carboxylate group on cinnamic acid, the prenyl group, and either retention of 4-dihydrocinnamoyloxy group or acetate substituent on cinnamic acid are important to maintain the high potency and selectivity for AKR1C3.
- 193Verma, K.; Zang, T.; Gupta, N.; Penning, T. M.; Trippier, P. C. Selective AKR1C3 inhibitors potentiate chemotherapeutic activity in multiple acute myeloid leukemia (AML) cell lines. ACS Med. Chem. Lett. 2016, 7, 774– 779, DOI: 10.1021/acsmedchemlett.6b00163[ACS Full Text], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVektrfI&md5=433b508f945e347873b1a72f1941af30Selective AKR1C3 Inhibitors Potentiate Chemotherapeutic Activity in Multiple Acute Myeloid Leukemia (AML) Cell LinesVerma, Kshitij; Zang, Tianzhu; Gupta, Nehal; Penning, Trevor M.; Trippier, Paul C.ACS Medicinal Chemistry Letters (2016), 7 (8), 774-779CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We report the design, synthesis, and evaluation of potent and selective inhibitors of aldo-keto reductase 1C3 (AKR1C3), an important enzyme in the regulatory pathway controlling proliferation, differentiation, and apoptosis in myeloid cells. Combination treatment with the nontoxic AKR1C3 inhibitors and etoposide or daunorubicin in acute myeloid leukemia cell lines, elicits a potent adjuvant effect, potentiating the cytotoxicity of etoposide by up to 6.25-fold and the cytotoxicity of daunorubicin by >10-fold. The results validate AKR1C3 inhibition as a common adjuvant target across multiple AML subtypes. These compds. in coadministration with chemotherapeutics in clin. use enhance therapeutic index and may avail chemotherapy as a treatment option to the pediatric and geriatric population currently unable to tolerate the side effects of cancer drug regimens.
- 194Pandi-Perumal, S. R.; Srinivasan, V.; Maestroni, G. J. M.; Cardinali, D. P.; Poeggeler, B.; Hardeland, R. Melatonin: nature’s most versatile biological signal?. FEBS J. 2006, 273, 2813– 2838, DOI: 10.1111/j.1742-4658.2006.05322.x[Crossref], [PubMed], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XnvFaisr4%253D&md5=964603edf0a241876aeb516cbf610159Melatonin. Nature's most versatile biological signal?Pandi-Perumal, S. R.; Srinivasan, V.; Maestroni, G. J. M.; Cardinali, D. P.; Poeggeler, B.; Hardeland, R.FEBS Journal (2006), 273 (13), 2813-2838CODEN: FJEOAC; ISSN:1742-464X. (Blackwell Publishing Ltd.)A review. Melatonin is a ubiquitous mol. and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a no. of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronol. pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiol. functions through paracrine signaling. Melatonin has also been extd. from the seeds and leaves of a no. of plants and its concn. in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiol. functions. In addn. to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong anti-apoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic mol.' in seasonal reprodn. has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiol. functions.
- 195Jockers, R.; Maurice, P.; Boutin, J. A.; Delagrange, P. Melatonin receptors, heterodimerization, signal transduction and binding sites: what’s new?. Br. J. Pharmacol. 2008, 154, 1182– 1195, DOI: 10.1038/bjp.2008.184[Crossref], [PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosVCjtLk%253D&md5=285de0da9971c744d5620dc33aa92e97Melatonin receptors, heterodimerization, signal transduction and binding sites: what's new?Jockers, R.; Maurice, P.; Boutin, J. A.; Delagrange, P.British Journal of Pharmacology (2008), 154 (6), 1182-1195CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)A review. Melatonin is a neurohormone that has been claimed to be involved in a wide range of physiol. functions. Nevertheless, for most of its effects, the mechanism of action is not really known. In mammals, two melatonin receptors, MT1 and MT2, have been cloned. They belong to the G-protein-coupled receptor (GPCR) superfamily. They share some specific short amino-acid sequences, which suggest that they represent a specific subfamily. Another receptor from the same subfamily, the melatonin-related receptor has been cloned in different species including humans. This orphan receptor also named GPR50 does not bind melatonin and its endogenous ligand is still unknown. Nevertheless, this receptor has been shown to behave as an antagonist of the MT1 receptor, which opens new pharmacol. perspectives for GPR50 despite the lack of endogenous or synthetic ligands. Moreover, MT1 and MT2 interact together through the formation of heterodimers at least in cells transfected with the cDNA of these two receptors. Lastly, signaling complexes assocd. with MT1 and MT2 receptors are starting to be deciphered. A third melatonin-binding site has been purified and characterized as the enzyme quinone reductase 2 (QR2). Inhibition of QR2 by melatonin may explain melatonin's protective effect that has been reported in different animal models and that is generally assocd. with its well-documented antioxidant properties.
- 196Li, Y.; Li, S.; Zhou, Y.; Meng, X.; Zhang, J. J.; Xu, D. P.; Li, H. B. Melatonin for the prevention and treatment of cancer. Oncotarget 2017, 8, 39896– 39921, DOI: 10.18632/oncotarget.16379[Crossref], [PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cvosVGmtw%253D%253D&md5=afda46503108e4e492f7d50a56ad98f4Melatonin for the prevention and treatment of cancerLi Ya; Zhou Yue; Meng Xiao; Zhang Jiao-Jiao; Xu Dong-Ping; Li Hua-Bin; Li Sha; Li Hua-BinOncotarget (2017), 8 (24), 39896-39921 ISSN:.The epidemiological studies have indicated a possible oncostatic property of melatonin on different types of tumors. Besides, experimental studies have documented that melatonin could exert growth inhibition on some human tumor cells in vitro and in animal models. The underlying mechanisms include antioxidant activity, modulation of melatonin receptors MT1 and MT2, stimulation of apoptosis, regulation of pro-survival signaling and tumor metabolism, inhibition on angiogenesis, metastasis, and induction of epigenetic alteration. Melatonin could also be utilized as adjuvant of cancer therapies, through reinforcing the therapeutic effects and reducing the side effects of chemotherapies or radiation. Melatonin could be an excellent candidate for the prevention and treatment of several cancers, such as breast cancer, prostate cancer, gastric cancer and colorectal cancer. This review summarized the anticancer efficacy of melatonin, based on the results of epidemiological,experimental and clinical studies, and special attention was paid to the mechanisms of action.
- 197Alghamdi, B. S. The neuroprotective role of melatonin in neurological disorders. J. Neurosci. Res. 2018, 96, 1136– 1149, DOI: 10.1002/jnr.24220[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjs1amt7w%253D&md5=58edf0fc7b3b82a725505261df9eb56fThe neuroprotective role of melatonin in neurological disordersAlghamdi, B. S.Journal of Neuroscience Research (2018), 96 (7), 1136-1149CODEN: JNREDK; ISSN:0360-4012. (Wiley-Blackwell)A review. Melatonin is a neurohormone secreted from the pineal gland and has a wide-ranging regulatory and neuroprotective role. It has been reported that melatonin level is disturbed in some neurol. conditions such as stroke, Alzheimer's disease, and Parkinson's disease, which indicates its involvement in the pathophysiol. of these diseases. Its properties qualify it to be a promising potential therapeutic neuroprotective agent, with no side effects, for some neurol. disorders. This review discusses and localizes the effect of melatonin in the pathophysiol. of some diseases.
- 198Karamitri, A.; Jockers, R. Melatonin in type 2 diabetes mellitus and obesity. Nat. Rev. Endocrinol. 2019, 15, 105– 125, DOI: 10.1038/s41574-018-0130-1[Crossref], [PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFWrtLbE&md5=5782714fe2669b78fe02e75089cd9e95Melatonin in type 2 diabetes mellitus and obesityKaramitri, Angeliki; Jockers, RalfNature Reviews Endocrinology (2019), 15 (2), 105-125CODEN: NREABD; ISSN:1759-5029. (Nature Research)A review. Despite considerable advances in the past few years, obesity and type 2 diabetes mellitus (T2DM) remain two major challenges for public health systems globally. In the past 9 years, genome-wide assocn. studies (GWAS) have established a major role for genetic variation within the MTNR1B locus in regulating fasting plasma levels of glucose and in affecting the risk of T2DM. This discovery generated a major interest in the melatonergic system, in particular the melatonin MT2 receptor (which is encoded by MTNR1B). In this Review, we discuss the effect of melatonin and its receptors on glucose homeostasis, obesity and T2DM. Preclin. and clin. post-GWAS evidence of frequent and rare variants of the MTNR1B locus confirmed its importance in regulating glucose homeostasis and T2DM risk with minor effects on obesity. However, these studies did not solve the question of whether melatonin is beneficial or detrimental, an issue that will be discussed in the context of the peculiarities of the melatonergic system. Melatonin receptors might have therapeutic potential as they belong to the highly druggable G protein-coupled receptor superfamily. Clarifying the precise role of melatonin and its receptors on glucose homeostasis is urgent, as melatonin is widely used for other indications, either as a prescribed medication or as a supplement without medical prescription, in many countries in Europe and in the USA.
- 199Leclerc, V.; Fourmaintraux, E.; Depreux, P.; Lesieur, D.; Morgan, P.; Howell, H. E.; Renard, P.; Caignard, D. H.; Pfeiffer, B.; Delagrange, P.; Guardiola-Lemaitre, B.; Andrieux, J. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. Bioorg. Med. Chem. 1998, 6, 1875– 1887, DOI: 10.1016/S0968-0896(98)00147-3[Crossref], [PubMed], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntlOhtbs%253D&md5=6ed68fd9dbf928caa550601c70cb3200Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligandsLeclerc, Veronique; Fourmaintraux, Eric; Depreux, Patrick; Lesieur, Daniel; Morgan, Peter; Howell, H. Edward; Renard, Pierre; Caignard, Daniel-Henri; Pfeiffer, Bruno; Delagrange, Philippe; Guardiola-Lemaitre, Beatrice; Andrieux, JeanBioorganic & Medicinal Chemistry (1998), 6 (10), 1875-1887CODEN: BMECEP; ISSN:0968-0896. (Elsevier Science Ltd.)A previous paper reported the synthesis of melatonin receptor ligands. In order to complete the structure-activity relationships and to obtain antagonists to the melatonin receptor, a new series of naphthalenic analogs of melatonin have been synthesized. Modifications include deletion of the 7-methoxy group, replacement of the ethylene moiety, replacement of the amidic function by bioisosteres, and replacement of the naphthalenic nucleus by other bicyclic rings. Almost all the structural modifications lead to decreased affinity for the melatonin receptor. However, the N-n-Pr urea deriv. is a very potent ligand at this receptor (pKi = 14.3). Most interestingly deletion of the methoxy group resulted in the first antagonist in this series. This mol., a Pr deriv., or N-[2-(1-naphthyl)-ethyl]cyclobutyl carboxamide has been selected for preclin. development.
- 200Morgan, P. J.; Williams, L. M.; Davidson, G.; Lawson, W.; Howell, E. Melatonin receptors on ovine pars tuberalis: characterization and autoradiographicai localization. J. Neuroendocrinol. 1989, 1, 1– 4, DOI: 10.1111/j.1365-2826.1989.tb00068.x[Crossref], [PubMed], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXhs1Gmuw%253D%253D&md5=a5d805b08a2d01a3bd1579750b9fd469Melatonin receptors on ovine pars tuberalis: characterization and autoradiographical localizationMorgan, Peter J.; Williams, Lynda M.; Davidson, Gary; Lawson, Wilfred; Howell, EdwardJournal of Neuroendocrinology (1989), 1 (1), 1-4CODEN: JOUNE2; ISSN:0953-8194.The highly specific ligand [125I]melatonin was used to demonstrate that it binds exclusively, with very high affinity, to the pars tuberalis but not the pars distalis of the adult sheep adenohypophysis. Evidently, the PT has a distinct role in relation to melatonin action and seasonal reprodn.
- 201He, P.; Ouyang, X.; Zhou, S.; Yin, W.; Tang, C.; Laudon, M.; Tian, S. A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer’ disease. Horm. Behav. 2013, 64, 1– 7, DOI: 10.1016/j.yhbeh.2013.04.009[Crossref], [PubMed], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVOjsb%252FO&md5=606e93bc9b1833602139c79e501b1b23A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer' diseaseHe, Pingping; Ouyang, Xinping; Zhou, Shouhong; Yin, Weidong; Tang, Chaoke; Laudon, Moshe; Tian, ShaowenHormones and Behavior (2013), 64 (1), 1-7CODEN: HOBEAO; ISSN:0018-506X. (Elsevier Inc.)Previous studies have shown that melatonin is implicated in modulating learning and memory processing. Melatonin also exerts neuroprotective activities against Aβ-induced injury in vitro and in vivo. Neu-P11 (piromelatine, N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2-carboxamide) is a novel melatonin (MT1/MT2) receptor agonist and a serotonin 5-HT1A/1D receptor agonist recently developed for the treatment of insomnia. In the present study we firstly investigated whether Neu-P11 and melatonin enhance memory performance in the novel object recognition (NOR) task in rats, and then assessed whether Neu-P11 and melatonin improve neuronal and cognitive impairment in a rat model of Alzheimer' disease (AD) induced by intrahippocampal Aβ(1-42) injection. The results showed that a single morning or afternoon administration of Neu-P11 enhanced object recognition memory measured at 4 or 24 h after training. Melatonin was effective in the memory facilitating effects only when administered in the afternoon. Further results showed that intrahippocampal Aβ(1-42) injection resulted in hippocampal cellular loss, as well as decreased learning ability and memory in the Y maze and NOR tasks in rats. Neu-P11 but not melatonin attenuated cellular loss and cognitive impairment in the rat AD model. The current data suggest that Neu-P11 may serve as a novel agent for the treatment of AD.
- 202Tian, S. W.; Laudon, M.; Han, L.; Gao, J.; Huang, F. L.; Yang, Y. F.; Deng, H. F. Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent models. Acta Pharmacol. Sin. 2010, 31, 775– 783, DOI: 10.1038/aps.2010.80[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXotlSntbc%253D&md5=0e967edd638bb89b6bd19e51d771ac49Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent modelsTian, Shao-wen; Laudon, Moshe; Han, Li; Gao, Jun; Huang, Fu-lian; Yang, Yu-feng; Deng, Hai-fengActa Pharmacologica Sinica (2010), 31 (7), 775-783CODEN: APSCG5; ISSN:1671-4083. (Nature Publishing Group)Aim: To investigate the potential antidepressant and anxiolytic effects of Neu-P11, a novel melatonin agonist, in two models of depression in rats and a model of anxiety in mice. Methods: In the learned helplessness test (LH), Neu-P11 or melatonin (25-100 mg/kg, i.p.) was administered to rats 2 h before the beginning of the dark phase once a day for 5 days and the no. of escape failures and intertrial crossings during the test phase were recorded. In the forced swimming test (FST), rats received a single or repeated administration of Neu-P11 (25-100 mg/kg, i.p.). The total period of immobility during the test phase was assessed. In the elevated plus-maze test (EPM), mice were treated with Neu-P11 (25-100 mg/kg, i.p.) or melatonin in the morning or in the evening and tested 2 h later. The percentage of time spent in the open arms and the open arms entries were assessed. Results: In the LH test, Neu-P11 but not melatonin significantly decreased the escape deficit and had no effect on the intertrial crossings. In the FST, a single or repeated administration of Neu-P11, either in the morning or in the evening, significantly decreased the duration of immobility. In the EPM test, Neu-P11 significantly increased the percentage of time spent in the open arms and the open arms entries irresp. to the time of administration. Melatonin was effective only when administered in the afternoon. Conclusion: The results demonstrate that Neu-P11 exerts antidepressant and anxiolytic activities in rodent models.
- 203Rami, M.; Landagaray, E.; Ettaoussi, M.; Boukhalfa, K.; Caignard, D. H.; Delagrange, P.; Berthelot, P.; Yous, S. Novel conformationally constrained analogues of agomelatine as new melatoninergic ligands. Molecules 2013, 18, 154– 166, DOI: 10.3390/molecules18010154[Crossref], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpsFemsw%253D%253D&md5=3742d28bfe6f3f12b98905b07429bde7Novel conformationally constrained analogues of agomelatine as new melatoninergic ligandsRami, Marouan; Landagaray, Elodie; Ettaoussi, Mohamed; Boukhalfa, Koussayla; Caignard, Daniel-Henri; Delagrange, Philippe; Berthelot, Pascal; Yous, SaidMolecules (2013), 18 (), 154-166CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Novel conformationally restricted analogs of agomelatine were synthesized and pharmacol. evaluated at MT1-receptor ligands and MT2 melatoninergic receptor ligands. s. Replacement of the N-acetyl side chain of agomelatine by oxathiadiazole 2-oxide, oxadiazolone, tetrazole, oxazolidinone, pyrrolidinone, imidazolidinedione, thiazole, and isoxazole groups led to a decrease of the melatoninergic binding affinity, particularly at MT1. Two compds. exhibiting nanomolar affinity towards the MT2 receptors subtypes have shown the most interesting pharmacol. results of this series with the appearance of a weak MT2-selectivity. The title compds. thus formed included an imidazolidinedione analog (I) [5-[(7-methoxy-1-naphthalenyl)methyl]-2,4-imidazolidinedione] and related substances, such as a thiazole analog, isoxazole analog, oxazole analog, triazole analog.
- 204Pala, D.; Lodola, A.; Bedini, A.; Spadoni, G.; Rivara, S. Homology models of melatonin receptors: challenges and recent advances. Int. J. Mol. Sci. 2013, 14, 8093– 8121, DOI: 10.3390/ijms14048093[Crossref], [PubMed], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntlCmtbk%253D&md5=09a98e3c67eeb7bcb0119d5c91a818e5Homology models of melatonin receptors: challenges and recent advancesPala, Daniele; Lodola, Alessio; Bedini, Annalida; Spadoni, Gilberto; Rivara, SilviaInternational Journal of Molecular Sciences (2013), 14 (4), 8093-8121, 29 pp.CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a no. of different MT1 and MT2 receptor homol. models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described and they will be discussed in light of the available information from mutagenesis expts. and ligand-based pharmacophore models. The ability of these ligand-receptor complexes to rationalize structure-activity relationships of known series of melatonergic compds. will be commented upon.
- 205Jagtap, A. D.; Kondekar, N. B.; Sadani, A. A.; Chern, J. W. Ureas: applications in drug design. Curr. Med. Chem. 2017, 24, 622– 651, DOI: 10.2174/0929867323666161129124915[Crossref], [PubMed], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlsVChurg%253D&md5=a3b883c65d950d7e698b40bb71a7f938Ureas: Applications in Drug DesignJagtap, Ajit Dhananjay; Kondekar, Nagendra Bharatrao; Sadani, Amit A.; Chern, Ji-WangCurrent Medicinal Chemistry (2017), 24 (6), 622-651CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)The unique hydrogen binding capabilities of ureas make them an important functional group to make drug-target interactions and thus incorporated in small mols. displaying broad range of bioactivities. The related research and numerous excellent achievements of ureas applicability in drug design for the modulation of selectivity, stability, toxicity and pharmacokinetic profile of lead mols. have become active topic. This review aims to provide insights in to the significance of urea in drug design by summarizing successful studies of various urea derivs. as modulators biol. targets (viz. kinases, NAMPT, sol. epoxide hydrolases, mTOR, proteases, gyrB/parE, and epigenetic enzymes such as HDAC, PRMT or DOT1L etc.). The findings of this review confirm the importance of urea moiety in medicinal chem. and stimulate its use as a structural motif with rational decision making approach.
- 206Ghosh, A. K.; Brindisi, M. Urea derivatives in modern drug discovery and medicinal chemistry. J. Med. Chem. 2020, 63 (6), 2751– 2788, DOI: 10.1021/acs.jmedchem.9b01541[ACS Full Text], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1GksbrF&md5=f888b6af362248abcb16573d8cb69e6dUrea Derivatives in Modern Drug Discovery and Medicinal ChemistryGhosh, Arun K.; Brindisi, MargheritaJournal of Medicinal Chemistry (2020), 63 (6), 2751-2788CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The urea functionality is inherent to numerous bioactive compds., including a variety of clin. approved therapies. Urea-contg. compds. are increasingly used in medicinal chem. and drug design in order to establish key drug-target interactions and also to fine-tune crucial drug-like properties. In this perspective, physicochem. and conformational properties of urea derivs. are highlighted. Outlines of traditional reagents and chem. procedures for the prepn. of ureas are provided. Also, newly developed methodologies mainly aimed at overcoming safety issues assocd. with traditional synthesis are discussed. Finally, a broad overview of urea-based medicinally relevant compds., ranging from approved drugs to recent medicinal chem. developments is provided.
- 207Roark, W. H.; Roth, B. D.; Holmes, A.; Trivedi, B. K.; Kieft, K. A.; Essenburg, A. D.; Krause, B. R.; Stanfield, R. L. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 2. modification of fatty acid anilide ACAT inhibitors: bioisosteric replacement of the amide bond. J. Med. Chem. 1993, 36, 1662– 1668, DOI: 10.1021/jm00063a016[ACS Full Text], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXksV2jsbo%253D&md5=deeb4c1a41e69dcacff1fb51b3ff1e46Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 2. Modification of fatty acid anilide ACAT inhibitors: bioisosteric replacement of the amide bondRoark, W. Howard; Roth, Bruce D.; Holmes, Ann; Trivedi, Bharat K.; Kieft, Karen A.; Essenburg, Arnold D.; Krause, Brian R.; Stanfield, Richard L.Journal of Medicinal Chemistry (1993), 36 (11), 1662-8CODEN: JMCMAR; ISSN:0022-2623.In order to further define the structural features necessary for potent inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) in vitro and cholesterol lowering in vivo, a systematic study of bioisosteric replacements for the amide bond in our previously identified series of fatty acid anilide ACAT inhibitors was undertaken. In order to further define the structural features necessary for potent inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) in vitro and cholesterol lowering in vivo, a systematic study of bioisosteric replacements for the amide bond in our previously identified series of fatty acid anilide ACAT inhibitors was undertaken. Only replacement of amide bonds with isosteres having both hydrogen bond donor and acceptor functionalities yielded compds. retaining ACAT inhibitory activity. Replacement of the amide bond with the urea bioisostere yielded compds. that were potent ACAT inhibitors in vitro and efficacious hypocholesterolemic agents in vivo. Examn. of the structure activity relationships in the Ph ring and alkyl portion of the N-phenyl-N'-alkylureas revealed that 2,6-diisopropyl substitution was optimal in the Ph ring, for example in .N-(2,6-diisopropylphenyl)-N'-decylurea (I). When the 2,6-diisopropyl moiety was kept const., potency in vitro and in vivo was maintained with straight and branched alkyl groups from 6 to 18 carbons in length. Only replacement of amide bonds with isosteres having both hydrogen bond donor and acceptor functionalities yielded compds. retaining ACAT inhibitory activity. Replacement of the amide bond with the urea bioisostere yielded compds. that were potent ACAT inhibitors in vitro and efficacious hypocholesterolemic agents in vivo. Examn. of the structure activity relationships in the Ph ring and alkyl portion of the N-phenyl-N'-alkylureas revealed that 2,6-diisopropyl substitution was optimal in the Ph ring. When the 2,6-diisopropyl moiety was kept const., potency in vitro and in vivo was maintained with straight and branched alkyl groups from 6 to 18 carbons in length.
- 208Augelli-Szafran, C. E.; Blankley, C. J.; Roth, B. D.; Trivedi, B. K.; Bousley, R. F.; Essenburg, A. D.; Hamelehle, K. L.; Krause, B. R.; Stanfield, R. L. Inhibitors of acyl-CoA:cholesterol acyltransferase. 5. identification and structure-activity relationships of novel beta-ketoamides as hypocholesterolemic agents. J. Med. Chem. 1993, 36, 2943– 2949, DOI: 10.1021/jm00072a014[ACS Full Text], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXlvFGis7Y%253D&md5=f81c99fccade9b20cf5e4781ab274706Inhibitors of acyl-CoA:cholesterol acyltransferase. 5. Identification and structure-activity relationships of novel β-keto amides as hypocholesterolemic agentsAugelli-Szafran, Corinne E.; Blankley, C. John; Roth, Bruce D.; Trivedi, Bharat K.; Bousley, Richard F.; Essenburg, Arnold D.; Hamelehle, Katherine L.; Krause, Brian R.; Stanfield, Richard L.Journal of Medicinal Chemistry (1993), 36 (20), 2943-9CODEN: JMCMAR; ISSN:0022-2623.A study of structure-activity relations of substituted β-ketoamide acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors (I, R1,R5,R6 = e.g., H or alkyl; R2,R3 = H or Me; R4 = C8-13 alkyl, Ph, CHPh2) and (II, X = O or NH, R = C5-6 alkyl or dodecyl; n = 1-3) was performed. Whereas the β-keto group was tolerated with no loss in activity, β-hydroxy and oxime moieties led to significantly reduced activity in vitro and in vivo. The most potent inhibitor from the acyclic series (III; IC50 = 0.006 μM) contained a C13-alkyl chain. III reduced plasma total cholesterol by 38% and 66% at 3 and 30 mg/kg, resp., in cholesterol-fed rats. Dimethylation α to the anilide core and subsequent N-methylation of the amide-NH decreased in vitro potency significantly. High potency was retained with inhibitors which incorporated the carbonyl into a lactam ring.
- 209Trivedi, B. K.; Holmes, A.; Stoeber, T. L.; Blankley, C. J.; Roark, W. H.; Picard, J. A.; Shaw, M. K.; Essenburg, A. D.; Stanfield, R. L.; Krause, B. R. Inhibitors of acyl-Coa:cholesterol acyltransferase. 4. a novel series of urea ACAT inhibitors as potential hypocholesterolemic agents. J. Med. Chem. 1993, 36, 3300– 3307, DOI: 10.1021/jm00074a011[ACS Full Text], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXlsVaqsg%253D%253D&md5=93453fd181d47a1dbd608ccb274652cfInhibitors of acyl-CoA:cholesterol acyltransferase. 4. A novel series of urea ACAT inhibitors as potential hypocholesterolemic agentsTrivedi, Bharat K.; Holmes, Ann; Stoeber, Terri L.; Blankley, C. John; Roark, W. Howard; Picard, Joseph A.; Shaw, Mary K.; Essenburg, Arnold D.; Stanfield, Richard L.; Krause, Brian R.Journal of Medicinal Chemistry (1993), 36 (22), 3300-7CODEN: JMCMAR; ISSN:0022-2623.A series of N-phenyl-N'-aralkyl- and N-phenyl-N'-(1-phenylcycloalkyl)ureas has been synthesized as inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). This intracellular enzyme is thought to be responsible for the esterification of dietary cholesterol; hence inhibition of this enzyme could reduce diet-induced hypercholesterolemia. For this series of compds., the in vitro ACAT inhibitory activity was improved by increasing the bulk of the 2,6-substituents on the Ph ring. Spacing of the arom. rings was crit. for the ACAT inhibitory activity. A Ph ring five atoms away from the requisite 2,6-diisopropylphenyl moiety was optimal for in vitro activity. Substitution α to the N'-Ph moiety enhanced in vitro potency. In the case of phenylcycloalkyl ureas, ACAT inhibitory activity was independent of the size of the cycloalkyl ring. From this series of analogs, compd. I, which had excellent in vitro potency for inhibiting ACAT, was found to lower plasma cholesterol by 73% in vivo when administered in the diet at 50 mg/kg in an animal model of hypercholesterolemia. In this model, compd. I lowered plasma cholesterol dose dependently and was as efficacious as the Lederle ACAT inhibitor CL 277082.
- 210Lebreton, L.; Annat, J.; Derrepas, P.; Dutartre, P.; Renaut, P. Structure-immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 1. structural modifications of the hydroxyglycine moiety. J. Med. Chem. 1999, 42, 277– 290, DOI: 10.1021/jm980431g[ACS Full Text], [CAS], Google Scholar210https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXhslOhtg%253D%253D&md5=93b77bb48c6d2fa8cfa1c3bcf4aa3e84Structure-Immunosuppressive Activity Relationships of New Analogs of 15-Deoxyspergualin. 1. Structural Modifications of the Hydroxyglycine MoietyLebreton, Luc; Annat, Jocelyne; Derrepas, Philippe; Dutartre, Patrick; Renaut, PatriceJournal of Medicinal Chemistry (1999), 42 (2), 277-290CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of new analogs of 15-deoxyspergualin (DSG), an immunosuppressive agent currently commercialized in Japan, was synthesized and tested in a graft-vs.-host disease (GVHD) model in mice. Using the general concept of bioisosteric replacement, variations of the hydroxyglycine central "C" region were made in order to det. its optimum structure in terms of in vivo immunosuppressive activity. By this way, the malonic deriv. H2NC(=NH)NH(CH2)6NHCOCH2CONH(CH2)4NH(CH2)3NH2 (I) was discovered as the first example of a new series of potent immunosuppressive agents encompassing a retro-amide bond linked to the hexyl-guanidino moiety. Structure-activity relationships of this series were studied by synthesizing compds. H2NC(=NH)NH(CH2)6NHCOACONH(CH2)4NH(CH2)3NH2 (II) [A = CH2, (Z)-CH=CH, (CH2)2, (CH2)3, bond, (E)-CH=CH, CH(CH2Ph), CH(Me), CH(OMe), CH2CH(OH), CH(Ph), C(CH2OH)2, CH(Et), C(Me)2, CH(NHAc), CH(NH2), C(OMe)2, CH(OCH2Ph), CH(OH), CH(F)]. Variation of the "right-amide" of I led to the urea H2NC(=NH)NH(CH2)6NHCOCH2NHCONH(CH2)4NH(CH2)3NH2 and the carbamates H2NC(=NH)NH(CH2)6NHCOCH2NHCOO(CH2)4NH(CH2)3NH2 and H2NC(=NH)NH(CH2)6NHCOCH2OCONH(CH2)4NH(CH2)3NH2 (III) which proved to be equally active as DSG in our GVHD model. III was found to be the most potent deriv., being slightly more active than DSG in a heart allotransplantation model in rats. Due to the absence of chiral center in its structure and to its improved chem. stability compared to DSG, III was selected as a candidate for clin. evaluation.
- 211Chan, L.; Jin, H.; Stefanac, T.; Lavallee, J. F.; Falardeau, G.; Wang, W.; Bedard, J.; May, S.; Yuen, L. Discovery of 1,6-naphthyridines as a novel class of potent and selective human cytomegalovirus inhibitors. J. Med. Chem. 1999, 42, 3023– 3025, DOI: 10.1021/jm9902483[ACS Full Text], [CAS], Google Scholar211https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXksF2lu78%253D&md5=d2c1ab14066985ba2e9306901cb37fceDiscovery of 1,6-Naphthyridines as a Novel Class of Potent and Selective Human Cytomegalovirus InhibitorsChan, Laval; Jin, Haolun; Stefanac, Tomislav; Lavallee, Jean-Francois; Falardeau, Guy; Wang, Wei; Bedard, Jean; May, Suzanne; Yuen, LeonardJournal of Medicinal Chemistry (1999), 42 (16), 3023-3025CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The design and synthesis of analogs of 1,6-naphthyridine as human cytomegalovirus inhibitors as well as the results of preliminary structure-activity relation (SAR) studies are described. The SAR investigation suggests that an isopropoxy group at the ortho position and substitution at C-8 are highly desirable.
- 212Chan, L.; Jin, H.; Stefanac, T.; Wang, W.; Lavallee, J. F.; Bedard, J.; May, S. Isoquinoline-6-carboxamides as potent and selective anti-human cytomegalovirus (HCMV) inhibitors. Bioorg. Med. Chem. Lett. 1999, 9, 2583– 2586, DOI: 10.1016/S0960-894X(99)00435-7[Crossref], [PubMed], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmtFCitrw%253D&md5=ccf74cabd354a03db550b009442a8c6fIsoquinoline-6-carboxamides as potent and selective anti-human cytomegalovirus (HCMV) inhibitorsChan, Laval; Jin, Haolun; Stefanac, Tomislav; Wang, Wei; Lavallee, Jean-Francois; Bedard, Jean; May, SuzanneBioorganic & Medicinal Chemistry Letters (1999), 9 (17), 2583-2586CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Structure-activity relationship studies on newly identified anti-HCMV compds., the 1,6-naphthyridines led to the identification of isoquinoline-6-carboxamides as potent and selective anti-HCMV agents.
- 213Chan, L.; Stefanac, T.; Lavallee, J. F.; Jin, H.; Bedard, J.; May, S.; Falardeau, G. Design and synthesis of new potent human cytomegalovirus (HCMV) inhibitors based on internally hydrogen-bonded 1,6-naphthyridines. Bioorg. Med. Chem. Lett. 2001, 11, 103– 105, DOI: 10.1016/S0960-894X(00)00607-7[Crossref], [PubMed], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXotlKnug%253D%253D&md5=4626a7f37f6207672b925d79c07c0164Design and synthesis of new potent human cytomegalovirus (HCMV) inhibitors based on internally hydrogen-bonded 1,6-naphthyridinesChan, L.; Stefanac, T.; Lavallee, J.-F.; Jin, H.; Bedard, J.; May, S.; Falardeau, G.Bioorganic & Medicinal Chemistry Letters (2001), 11 (2), 103-105CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)1,6-Naphthyridine-2-carboxylic acid benzylamides are potent anti-HCMV compds. Replacement of the amide moiety by other groups contg. internal hydrogen bonds was undertaken to extend the structure-activity relationship. The results indicated that the urea derivs. showed very good activity.
- 214Bielawska, A.; Greenberg, M. S.; Perry, D.; Jayadev, S.; Shayman, J. A.; McKay, C.; Hannun, Y. A. (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol as an inhibitor of ceramidase. J. Biol. Chem. 1996, 271, 12646– 12654, DOI: 10.1074/jbc.271.21.12646[Crossref], [PubMed], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjtFantLg%253D&md5=1ed01f1936e1d2a9dcbd9b4b137ebbaa(1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol as an inhibitor of ceramidaseBielawska, Alicja; Greenberg, Mathew S.; Perry, David; Jayadev, Supriya; Shayman, James A.; McKay, Charles; Hannun, Yusuf A.Journal of Biological Chemistry (1996), 271 (21), 12646-12654CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The cellular and biochem. activities of the ceramide analog, (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol (D-e-MAPP), were examd. The addn. of 5 μM D-e-MAPP to HL-60 human promyelocytic leukemia cells resulted in a concn.- and time-dependent growth suppression accompanied by an arrest in the G0/G1 phase of the cell cycle; thus mimicking the action of exogenous ceramides. Its enantiomer, L-e-MAPP, was without effect. Two lines of evidence suggested that D-e-MAPP may not function as a direct analog of ceramide. First, D-e-MAPP possesses a stereochem. configuration opposite to that of D-erythro-ceramide. Second, D-e-MAPP failed to activate ceramide-activated phosphoprotein phosphatase in vitro. Therefore, the authors examd. if D-e-MAPP functioned indirectly by modulating endogenous ceramide levels. The addn. of D-e-MAPP to cells, but not L-e-MAPP, caused a time- and concn.-dependent elevation in endogenous ceramide levels reaching >3-fold over baseline following 24 h of treatment. Both D-e-MAPP and L-e-MAPP underwent similar uptake by HL-60 cells. D-E-MAPP was poorly metabolized, and remained intact in cells, whereas L-e-MAPP underwent a time- and concn.-dependent metab., primarily through N-deacylation. In vitro, L-e-MAPP was metabolized by alk. ceramidase to an extent similar to that seen with C16-ceramide. D-E-MAPP was not metabolized. Instead, D-e-MAPP inhibited alk. ceramidase activity in vitro with an IC50 of 1-5 μM. D-E-MAPP did not modulate the activity of other ceramide-metabolizing enzymes in vitro or in cells, and it was a poor inhibitor of acid ceramidase (IC50 > 500 μM). Finally, D-e-MAPP inhibited the metab. of L-e-MAPP in cells. These studies demonstrate that D-e-MAPP functions as an inhibitor of alk. ceramidase in vitro and in cells resulting in elevation in endogenous levels of ceramide with the consequent biol. effects of growth suppression and cell cycle arrest. These studies point to an important role for ceramidases in the regulation of endogenous levels of ceramide.
- 215Selzner, M.; Bielawska, A.; Morse, M. A.; Rudiger, H. A.; Sindram, D.; Hannun, Y. A.; Clavien, P. A. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res. 2001, 61, 1233– 1240[PubMed], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhsFSqsLg%253D&md5=8ac97b8e71f9bfd0dcbbf65975d5f167Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancerSelzner, Markus; Bielawska, Alicja; Morse, Michael A.; Rudiger, Hannes A.; Sindram, David; Hannun, Yusuf A.; Clavien, Pierre-AlainCancer Research (2001), 61 (3), 1233-1240CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Dysfunction in the physiol. pathways of programmed cell death may promote proliferation of malignant cells, and correction of such defects may selectively induce apoptosis in cancer cells. We measured the levels of ceramide, a candidate lipid mediator of apoptosis, in human metastatic colorectal cancer and tested in vitro and in vivo effects of various ceramide analogs in inducing apoptosis in metastatic colon cancer. Human colon cancer showed a >50% decrease in the cellular content of ceramide when compared with normal colon mucosa. Application of ceramide analogs and ceramidase inhibitors induced rapid cell death through activation of various proapoptotic mols., such as caspases and release of cytochrome c. Ceramidase inhibition increases the ceramide content of tumor cells, resulting in max. activation of the apoptotic cascade. Normal liver cells were completely resistant to inhibitors of ceramidases. Treatment of nude mice with B13, the most potent ceramidase inhibitor, completely prevented tumor growth using two different aggressive human colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogs of ceramide and inhibitors of ceramidases offer a promising therapeutic strategy with selective toxicity toward malignant but not normal cells. These studies also suggest that the ceramide content in cancer cells might be involved in the pathogenesis of tumor growth in vitro and in vivo.
- 216Lim, S.; Ryu, J. H.; Im, C.; Yim, C. B. Synthesis and cytotoxicity of new 3-alkyl-1-(1-methyl-2-phenylethyl)ureas related to ceramide. Arch. Pharmacal Res. 2003, 26, 270– 274, DOI: 10.1007/BF02976954[Crossref], [PubMed], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjvV2hu78%253D&md5=55eccdc6c14b998a3f92699eacf4b29aSynthesis and cytotoxicity of new 3-alkyl-1-(1-methyl-2-phenylethyl)ureas related to ceramideLim, Sejin; Ryu, Jae Hark; Im, Chaeuk; Yim, Chul BuArchives of Pharmacal Research (2003), 26 (4), 270-274CODEN: APHRDQ; ISSN:0253-6269. (Pharmaceutical Society of Korea)A series of new 3-alkyl-1-(1-methyl-2-phenylethyl)ureas related to ceramide was synthesized and evaluated for their in vitro cytotoxic activity against five human tumor cell lines. The urea analog of B13 showed comparable or slightly more potent cytotoxic activity as compared to B13, indicating that urea does appear to serve as a bioisostere of amide.
- 217Chang, Y. T.; Choi, J.; Ding, S.; Prieschl, E. E.; Baumruker, T.; Lee, J. M.; Chung, S. K.; Schultz, P. G. The synthesis and biological characterization of a ceramide library. J. Am. Chem. Soc. 2002, 124, 1856– 1857, DOI: 10.1021/ja017576o[ACS Full Text], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xps1aisg%253D%253D&md5=08e8c91553b4795803934d0671173366The Synthesis and Biological Characterization of a Ceramide LibraryChang, Young-Tae; Choi, Jaehwa; Ding, Sheng; Prieschl, Eva E.; Baumruker, Thomas; Lee, Jae-Mok; Chung, Sung-Kee; Schultz, Peter G.Journal of the American Chemical Society (2002), 124 (9), 1856-1857CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A facile synthesis of a combinatorial ceramide library and their activities in the NF-κB pathway and in apoptosis induction/prevention were demonstrated. A novel NF-κB activating mol. was discovered among ceramide contg. β-galactose, and the structural requirements of ceramides for apoptosis induction was elucidated.
- 218Bieberich, E.; Hu, B.; Silva, J.; MacKinnon, S.; Yu, R. K.; Fillmore, H.; Broaddus, W. C.; Ottenbrite, R. M. Synthesis and characterization of novel ceramide analogs for induction of apoptosis in human cancer cells. Cancer Lett. 2002, 181, 55– 64, DOI: 10.1016/S0304-3835(02)00049-6[Crossref], [PubMed], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XivVSgur0%253D&md5=14c8ac8985f6b711c5adb3ca2dbaf033Synthesis and characterization of novel ceramide analogs for induction of apoptosis in human cancer cellsBieberich, Erhard; Hu, Bin; Silva, Jeane; MacKinnon, Sarah; Yu, Robert K.; Fillmore, Helen; Broaddus, William C.; Ottenbrite, Raphael M.Cancer Letters (Shannon, Ireland) (2002), 181 (1), 55-64CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Science Ireland Ltd.)A variety of anti-cancer drugs elevate endogenous ceramide, thereby inducing apoptosis in tumor cells. Recently, we have introduced novel ceramide analogs of the β-hydroxy alkyl amide type, which trigger pro-apoptotic signaling pathways without prior elevation of endogenous ceramide. They induce apoptosis specifically in rapidly dividing neuroblastoma cells, but not in resting or differentiated cells. We characterize new ceramide mimics that have been derived from N-acylation of serinol , diethanolamine, propanolamine , and tris(hydroxy-methyl)methylamine with myristic, palmitic, or oleic acid. The water soly. of these compds. exceeds that of ceramide by more than 100-fold (up to 5 mM). Apoptosis of human neuroblastoma, glioma, medulloblastoma, and adenocarcinoma cells is induced by N-(2-hydroxy-1-(hydroxymethyl)ethyl)-palmitoylamide, C16-serinol, N-(2-hydroxy-1-(hydroxymethyl)ethyl)-oleoylamide, C18-serinol , N-bis(2-hydroxyethyl)-myristoyl-amide , and N-tris(hydroxymethyl)methyl-oleoylamide within 60 min of incubation, and is completed even after removal of the compd. from the medium. This is most likely due to a rapid uptake of the analogs followed by their slow release from the cells. Alteration of the acyl chain length to less than 14 methylene units, removal of the amino group, or reducing the no. of hydroxyalkyl residues to less than two significantly lowers or eliminates the pro-apoptotic potential of these compds. The target specificity of novel ceramide analogs for tumor cells, their water soly., and fast pro-apoptotic mechanism indicates a high therapeutic potential for cancer treatment.
- 219Wang, H.; Huwaimel, B.; Verma, K.; Miller, J.; Germain, T. M.; Kinarivala, N.; Pappas, D.; Brookes, P. S.; Trippier, P. C. Synthesis and antineoplastic evaluation of mitochondrial complex II (succinate dehydrogenase) inhibitors derived from Atpenin A5. ChemMedChem 2017, 12, 1033– 1044, DOI: 10.1002/cmdc.201700196[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpsFSqsLg%253D&md5=0c9cbe31b6f518e8a37fc1aa3beac02bSynthesis and Antineoplastic Evaluation of Mitochondrial Complex II (Succinate Dehydrogenase) Inhibitors Derived from Atpenin A5Wang, Hezhen; Huwaimel, Bader; Verma, Kshitij; Miller, James; Germain, Todd M.; Kinarivala, Nihar; Pappas, Dimitri; Brookes, Paul S.; Trippier, Paul C.ChemMedChem (2017), 12 (13), 1033-1044CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Mitochondrial complex II (CII) is an emerging target for numerous human diseases. Sixteen analogs of the CII inhibitor natural product atpenin A5 were prepd. to evaluate the structure-activity relationship of the C5 pyridine side chain. The side chain ketone moiety was detd. to be pharmacophoric, engendering a bioactive conformation. One analog, 1-(2,4-dihydroxy-5,6-dimethoxypyridin-3-yl)hexan-1-one (16 c), was found to have a CII IC50 value of 64 nM, to retain selectivity for CII over mitochondrial complex I (>156-fold), and to possess a ligand-lipophilicity efficiency (LLE) of 5.62, desirable metrics for a lead compd. This deriv. and other highly potent CII inhibitors show potent and selective anti-proliferative activity in multiple human prostate cancer cell lines under both normoxia and hypoxia, acting to inhibit mitochondrial electron transport.
- 220Patrick, D. A.; Wenzler, T.; Yang, S.; Weiser, P. T.; Wang, M. Z.; Brun, R.; Tidwell, R. R. Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiense. Bioorg. Med. Chem. 2016, 24, 2451– 2465, DOI: 10.1016/j.bmc.2016.04.006[Crossref], [PubMed], [CAS], Google Scholar220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmtlegtLk%253D&md5=d371dc632576f40e4002cd96b67c5a77Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiensePatrick, Donald A.; Wenzler, Tanja; Yang, Sihyung; Weiser, Patrick T.; Wang, Michael Zhuo; Brun, Reto; Tidwell, Richard R.Bioorganic & Medicinal Chemistry (2016), 24 (11), 2451-2465CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)2-(2-Benzamido)ethyl-4-phenylthiazole I was one of 1035 mols. (grouped into 115 distinct scaffolds) found to be inhibitory to Trypanosoma brucei, the pathogen causing human African trypanosomiasis, at concns. below 3.6 μM and nontoxic to mammalian (Huh7) cells in a phenotypic high-throughput screen of a 700,000 compd. library performed by the Genomics Institute of the Novartis Research Foundation (GNF). Compd. I and 72 analogs were synthesized in this lab. by one of two general pathways. These plus 10 com. available analogs were tested against T. brucei rhodesiense STIB900 and L6 rat myoblast cells (for cytotoxicity) in vitro. Forty-four derivs. were more potent than I, including eight with IC50 values below 100 nM. The most potent and most selective for the parasite was the urea analog 2-(2-piperidin-1-ylamido)ethyl-4-(3-fluorophenyl)thiazole II (IC50 = 9 nM, SI > 18,000). None of 33 compds. tested were able to cure mice infected with the parasite; however, seven compds. caused temporary redns. of parasitemia (≥97%) but with subsequent relapses. The lack of in vivo efficacy was at least partially due to their poor metabolic stability, as demonstrated by the short half-lives of 15 analogs against mouse and human liver microsomes.
- 221Patrick, D. A.; Gillespie, J. R.; McQueen, J.; Hulverson, M. A.; Ranade, R. M.; Creason, S. A.; Herbst, Z. M.; Gelb, M. H.; Buckner, F. S.; Tidwell, R. R. Urea derivatives of 2-aryl-benzothiazol-5-amines: a new class of potential drugs for human African trypanosomiasis. J. Med. Chem. 2017, 60, 957– 971, DOI: 10.1021/acs.jmedchem.6b01163[ACS Full Text], [CAS], Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitV2lt7nN&md5=aaf065ffbba4f4e702119f9c4c81d822Urea Derivatives of 2-Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African TrypanosomiasisPatrick, Donald A.; Gillespie, J. Robert; McQueen, Joshua; Hulverson, Matthew A.; Ranade, Ranae M.; Creason, Sharon A.; Herbst, Zackary M.; Gelb, Michael H.; Buckner, Frederick S.; Tidwell, Richard R.Journal of Medicinal Chemistry (2017), 60 (3), 957-971CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A previous publication from this lab explored the antitrypanosomal activities of novel derivs. of 2-(2-benzamido)ethyl-4-phenylthiazole, which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a no. of these compds., particularly the urea analogs, were quite potent, these mols. as a whole exhibited poor metabolic stability. The present work describes the synthesis of 65 new analogs arising from medicinal chem. optimization at different sites on the mol. The most promising compds. were the urea derivs. of 2-aryl-benzothiazol-5-amines. One such analog, (S)-2-(3,4-difluorophenyl)-5-(3-fluoro-N-pyrrolidylamido)benzothiazole (I) was chosen for in vivo efficacy studies based upon in vitro activity, metabolic stability, and brain penetration. This compd. attained 5/5 cures in murine models of both early and late stage human African trypanosomiasis, representing a new lead for the development of drugs to combat this neglected disease.
- 222He, J. B.; Ren, Y. L.; Sun, Q. S.; You, G. Y.; Zhang, L.; Zou, P.; Feng, L. L.; Wan, J.; He, H. W. Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors. Bioorg. Med. Chem. 2014, 22, 3180– 3186, DOI: 10.1016/j.bmc.2014.04.003[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnsVWqsbs%253D&md5=d5fdc148d0188b8f2c4ba703a0dc27a0Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitorsHe, Jun-Bo; Ren, Yan-Liang; Sun, Qiu-Shuang; You, Ge-Yun; Zhang, Li; Zou, Peng; Feng, Ling-Ling; Wan, Jian; He, Hong-WuBioorganic & Medicinal Chemistry (2014), 22 (12), 3180-3186CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)By targeting the ThDP binding site of Escherichia coli PDHc-E1, two new 'open-chain' classes of E. coli PDHc-E1 inhibitors, amide and urea derivs., were designed, synthesized, and evaluated. The amide deriv. I showed the most potent inhibition of E. coli PDHc-E1. The urea derivs. displayed more potent inhibitory activity than the corresponding amide derivs. with the same substituent. Mol. docking studies confirmed that the urea derivs. have more potency due to the two hydrogen bonds formed by two NH of urea with Glu522. The docking results also indicate it might help us to design more efficient PDHc-E1 inhibitors that could interact with Glu522.
- 223Ghosh, A. K.; Brindisi, M. Organic carbamates in drug design and medicinal chemistry. J. Med. Chem. 2015, 58, 2895– 2940, DOI: 10.1021/jm501371s[ACS Full Text], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXltVWkuw%253D%253D&md5=e3548247931b74b60e299ada1e27dda5Organic Carbamates in Drug Design and Medicinal ChemistryGhosh, Arun K.; Brindisi, MargheritaJournal of Medicinal Chemistry (2015), 58 (7), 2895-2940CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The carbamate group is a key structural motif in many approved drugs and prodrugs. There is an increasing use of carbamates in medicinal chem. and many derivs. are specifically designed to make drug-target interactions through their carbamate moiety. In this Perspective, we present properties and stabilities of carbamates, reagents and chem. methodologies for the synthesis of carbamates, and recent applications of carbamates in drug design and medicinal chem.
- 224Eckhardt, B. J.; Gulick, R. M. Drugs for HIV Infection. In Infectious Diseases, 4th ed.; Cohen, J., Opal, S. M., Powderly, W. G., Ed.; Elsevier Ltd., 2017; pp 1293– 1308.
- 225Bursavich, M. G.; Rich, D. H. Designing non-peptide peptidomimetics in the 21st century: inhibitors targeting conformational ensembles. J. Med. Chem. 2002, 45, 541– 558, DOI: 10.1021/jm010425b[ACS Full Text], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmsVantw%253D%253D&md5=8f00dc08b4d51c3021dd22a247bd56c0Designing Non-Peptide Peptidomimetics in the 21st Century: Inhibitors Targeting Conformational EnsemblesBursavich, Matthew G.; Rich, Daniel H.Journal of Medicinal Chemistry (2002), 45 (3), 541-558CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The goal of this Perspective is to outline for medicinal chemists the potential impact of receptor conformational mobility on rational drug design. While others have postulated receptor-based conformational selection of ligands and successfully designed inhibitors to emulate the -strand binding motif of native ligands , we show that novel protein conformations (not obsd. in either native or enzyme-inhibitor complexes) can be exploited to create nonpeptide enzyme inhibitors. We begin with a review of the development of peptidomimetic aspartic peptidase inhibitors and conclude with a new proposal for discovering fundamentally novel nonpeptide peptidomimetics by targeting conformational ensembles. Although we focus on the aspartic peptidases, the lessons derived therein are applicable to other peptidase and receptor-ligand systems.
- 226Ghosh, A. K.; Thompson, W. J.; McKee, S. P.; Duong, T. T.; Lyle, T. A.; Chen, J. C.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. 3-Tetrahydrofuran and pyran urethanes as high-affinity P2-ligands for HIV-1 protease inhibitors. J. Med. Chem. 1993, 36, 292– 294, DOI: 10.1021/jm00054a015[ACS Full Text], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXnsF2ltA%253D%253D&md5=f7046b53447fa4fdb531d0a18aa3643c3-Tetrahydrofuran and pyran urethanes as high-affinity P2-ligands for HIV-1 protease inhibitorsGhosh, Arun K.; Thompson, Wayne J.; McKee, Sean P.; Duong, Tien T.; Lyle, Terry A.; Chen, Jenny C.; Darke, Paul L.; Zugay, Joan A.; Emini, Emilio A.; et al.Journal of Medicinal Chemistry (1993), 36 (2), 292-4CODEN: JMCMAR; ISSN:0022-2623.Urethanes of 3-tetrahydrofurans and pyrans are high affinity P2 ligands for the HIV-1 protease inhibitors. Incorporation of these ligands provided potent inhibitors in the hydroxyethylene and hydroxyethylamine series with picomolar and nanomolar in vitro potencies. Substitution of t-butyloxycarbonyl group in I either with 3-tetrahydrofuranyl or 3-tetrahydropyranyl urethane not only increases intrinsic potency against the enzyme but generally leads to significant enhancement of antiviral potency as well. For example, II (IC50 <0.03 nM), obtained from com. available 3-(S)-hydroxytetrahydrofuran has prevented the spread of HIV-1 at a concn. of 3 nM (CIC95), a greater than 133-fold potency enhancement over inhibitor I.
- 227Thompson, W. J.; Ghosh, A. K.; Holloway, M. K.; Lee, H. Y.; Munson, P. M.; Schwering, J. E.; Wai, J.; Darke, P. L.; Zugay, J.; Emini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. 3′-Tetrahydrofuranylglycine as a novel, unnatural amino acid surrogate for asparagine in the design of inhibitors of the HIV protease. J. Am. Chem. Soc. 1993, 115, 801– 803, DOI: 10.1021/ja00055a069[ACS Full Text], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXht1Gjsbs%253D&md5=ea089d154011286bb01975430f67e6ef3'-Tetrahydrofuranylglycine as a novel, unnatural amino acid surrogate for asparagine in the design of inhibitors of the HIV proteaseThompson, Wayne J.; Ghosh, Arun K.; Holloway, M. Katharine; Lee, Hee Yoon; Munson, Peter M.; Schwering, John E.; Wai, Jenny; Darke, Paul L.; Zugay, Joan; et al.Journal of the American Chemical Society (1993), 115 (2), 801-3CODEN: JACSAT; ISSN:0002-7863.The stereoselective synthesis of the novel amino acids (3'R)- and (3'S)-tetrahydrofuranylglycine are reported. When incorporated into hydroxyethylamine transition state isostere I [R = (R)- and (S)-tetrahydrofuryl], substantial improvements in the inhibitory activities against HIV-1 and HIV-2 protease were obsd. relative to asparagine analog I (R = CH2CONH2) (Ro 31-8959).
- 228Ghosh, A. K.; Thompson, W. J.; Holloway, M. K.; McKee, S. P.; Duong, T. T.; Lee, H. Y.; Munson, P. M.; Smith, A. M.; Wai, J. M.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands. J. Med. Chem. 1993, 36, 2300– 2310, DOI: 10.1021/jm00068a006[ACS Full Text], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmtVegtbs%253D&md5=63f60b2efd113d4f2f51d869b4a4970bPotent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligandsGhosh, Arun K.; Thompson, Wayne J.; Holloway, M. Katharine; McKee, Sean P.; Duong, Tien T.; Lee, Hee Yoon; Munson, Peter M.; Smith, Anthony M.; Wai, Jenny M.; et al.Journal of Medicinal Chemistry (1993), 36 (16), 2300-10CODEN: JMCMAR; ISSN:0022-2623.A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compd. I (R = R1; Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compd. I (R = R1) with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compd. I; R = R2). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compd. I (R = R3) was 100-fold less potent than the 2S,3R-isomer (compd. I; R = R2). This stereochem. preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of I (R = R1) with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compd. I (R = R4) with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine deriv. at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compd. I (R = R5) in which the P2-P3-amide carbonyl has been removed. The resulting compd. I (R = R5) has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compd. I (R = R1).
- 229Morsy, A.; Trippier, P. C. Current and emerging pharmacological targets for the treatment of Alzheimer’s disease. J. Alzheimer's Dis. 2019, 72, S145– S176, DOI: 10.3233/JAD-190744[Crossref], [PubMed], [CAS], Google Scholar229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXosFKn&md5=95773aaf90f1f70bf76afd9112bfc776Current and Emerging Pharmacological Targets for the Treatment of Alzheimer's DiseaseMorsy, Ahmed; Trippier, Paul C.; Reddy, P. HemachandraJournal of Alzheimer's Disease (2019), 72 (s1), S145-S176CODEN: JADIF9; ISSN:1387-2877. (IOS Press)A review. No cure or disease-modifying therapy for Alzheimer's disease (AD) has yet been realized. However, a multitude of pharmacol. targets have been identified for possible engagement to enable drug discovery efforts for AD. Herein, we review these targets comprised around three main therapeutic strategies. First is an approach that targets the main pathol. hallmarks of AD: amyloid-β (Aβ) oligomers and hyperphosphorylated tau tangles which primarily focuses on reducing formation and aggregation, and/or inducing their clearance. Second is a strategy that modulates neurotransmitter signaling. Comprising this strategy are the cholinesterase inhibitors and N-methyl-D-aspartate receptor blockade treatments that are clin. approved for the symptomatic treatment of AD. Addnl. targets that aim to stabilize neuron signaling through modulation of neurotransmitters and their receptors are also discussed. Finally, the third approach comprises a collection of 'sensitive targets' that indirectly influence Aβ or tau accumulation. These targets are proteins that upon Aβ accumulation in the brain or direct Aβ-target interaction, a modification in the target's function is induced. The process occurs early in disease progression, ultimately causing neuronal dysfunction. This strategy aims to restore normal target function to alleviate Aβ-induced toxicity in neurons. Overall, we generally limit our anal. to targets that have emerged in the last decade and targets that have been validated using small mols. in in vitro and/or in vivo models. This review is not an exhaustive list of all possible targets for AD but serves to highlight the most promising and crit. targets suitable for small mol. drug intervention.
- 230Wong, G. T.; Manfra, D.; Poulet, F. M.; Zhang, Q.; Josien, H.; Bara, T.; Engstrom, L.; Pinzon-Ortiz, M.; Fine, J. S.; Lee, H. J.; Zhang, L.; Higgins, G. A.; Parker, E. M. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J. Biol. Chem. 2004, 279, 12876– 12882, DOI: 10.1074/jbc.M311652200[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXitl2gtb0%253D&md5=c06325df88c961273ac6229e4577d803Chronic Treatment with the γ-Secretase Inhibitor LY-411575 Inhibits β-Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell DifferentiationWong, Gwendolyn T.; Manfra, Denise; Poulet, Frederique M.; Zhang, Qi; Josien, Hubert; Bara, Thomas; Engstrom, Laura; Pinzon-Ortiz, Maria; Fine, Jay S.; Lee, Hu-Jung J.; Zhang, Lili; Higgins, Guy A.; Parker, Eric M.Journal of Biological Chemistry (2004), 279 (13), 12876-12882CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Inhibition of γ-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic β-amyloid (Aβ) peptides, is an attractive approach to the treatment of Alzheimer disease. In addn. to APP, however, several other γ-secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by γ-secretase inhibitors could lead to unintended biol. consequences. To study the in vivo consequences of γ-secretase inhibition, the γ-secretase inhibitor LY-411575 was administered to C57BL/6 and TgCRND8 APP transgenic mice for 15 days. Although most tissues were unaffected, doses of LY-411575 that inhibited Aβ prodn. had marked effects on lymphocyte development and on the intestine. LY-411575 decreased overall thymic cellularity and impaired intrathymic differentiation at the CD4-CD8-CD44+CD25+ precursor stage. No effects on peripheral T cell populations were noted following LY-411575 treatment, but evidence for the altered maturation of peripheral B cells was obsd. In the intestine, LY-411575 treatment increased goblet cell no. and drastically altered tissue morphol. These effects of LY-411575 were not seen in mice that were administered LY-D, a diastereoisomer of LY-411575, which is a very weak γ-secretase inhibitor. These studies show that inhibition of γ-secretase has the expected benefit of reducing Aβ in a murine model of Alzheimer disease but has potentially undesirable biol. effects as well, most likely because of the inhibition of Notch processing.
- 231Peters, J. U.; Galley, G.; Jacobsen, H.; Czech, C.; David-Pierson, P.; Kitas, E. A.; Ozmen, L. Novel orally active, dibenzazepinone-based γ-secretase inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 5918– 5923, DOI: 10.1016/j.bmcl.2007.07.078[Crossref], [PubMed], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFSitL7I&md5=6b1045f9decafe3f13320535b085b6e4Novel orally active, dibenzazepinone-based γ-secretase inhibitorsPeters, Jens-Uwe; Galley, Guido; Jacobsen, Helmut; Czech, Christian; David-Pierson, Pascale; Kitas, Eric A.; Ozmen, LaurenceBioorganic & Medicinal Chemistry Letters (2007), 17 (21), 5918-5923CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Structural modifications of the γ-secretase inhibitor, LY411575, led to a malonamide analog (S),(S)-1 with potent inhibitory activity in vitro, but disappointing activity in a mouse model of Alzheimer's disease. Identification and replacement of a metabolically labile position provided an improved compd. (R/S),(S)-13 with high in vitro activity (IC50 = 1.7 nM), and in vivo activity after oral administration (MED = 3 mg/kg). Further modifications gave an equipotent carbamate analog 14 (I) with improved mol. properties.
- 232Fransson, R.; Nordvall, G.; Bylund, J.; Carlsson-Jonsson, A.; Kratz, J. M.; Svensson, R.; Artursson, P.; Hallberg, M.; Sandstrom, A. Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1–7 analogues. ACS Med. Chem. Lett. 2014, 5, 1272– 1277, DOI: 10.1021/ml5002954[ACS Full Text], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVensrnJ&md5=7c45f3cbb6f0a62e6204a184a61d700eExploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance P 1-7 analoguesFransson, Rebecca; Nordvall, Gunnar; Bylund, Johan; Carlsson-Jonsson, Anna; Kratz, Jadel M.; Svensson, Richard; Artursson, Per; Hallberg, Mathias; Sandstroem, AnjaACS Medicinal Chemistry Letters (2014), 5 (12), 1272-1277CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compds. targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics the authors have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compd. Unfortunately, the pharmacophore of this compd. was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogs with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compd. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide.
- 233Kamenecka, T. M.; Park, Y. J.; Lin, L. S.; de Laszlo, S.; McCauley, E. D.; Van Riper, G.; Egger, L.; Kidambi, U.; Mumford, R. A.; Tong, S.; Tang, W.; Colletti, A.; Teffera, Y.; Stearns, R.; MacCoss, M.; Schmidt, J. A.; Hagmann, W. K. Amidines as amide bond replacements in VLA-4 antagonists. Bioorg. Med. Chem. Lett. 2004, 14, 2323– 2326, DOI: 10.1016/j.bmcl.2004.01.100[Crossref], [PubMed], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjtVegs7s%253D&md5=8f2974249b57ad785d8fd1a4d0f86d61Amidines as amide bond replacements in VLA-4 antagonistsKamenecka, Theodore M.; Park, You-Jung; Lin, Linus S.; de Laszlo, Stephen; McCauley, Ermenegilda D.; Van Riper, Gail; Egger, Linda; Kidambi, Usha; Mumford, Richard A.; Tong, Sharon; Tang, Wei; Colletti, Adria; Teffera, Yohannes; Stearns, Ralph; MacCoss, Malcolm; Schmidt, John A.; Hagmann, William K.Bioorganic & Medicinal Chemistry Letters (2004), 14 (9), 2323-2326CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)VLA-4 (α4β1, very late activating antigen-4), a key cell surface integrin plays an important role in inflammation by promoting leukocyte attachment and extravasation from the vasculature into the peripheral tissues. As such, VLA-4 antagonists may be useful in the treatment, prevention, and suppression of diseases where cell adhesion and migration are important such as asthma, rheumatoid arthritis, and multiple sclerosis. Herein, we report on the discovery, synthesis, and biol. evaluation of amidines as small mol. antagonists of VLA-4.
- 234Hagmann, W. K.; Durette, P. L.; Lanza, T.; Kevin, N. J.; de Laszlo, S. E.; Kopka, I. E.; Young, D.; Magriotis, P. A.; Li, B.; Lin, L. S.; Yang, G.; Kamenecka, T.; Chang, L. L.; Wilson, J.; MacCoss, M.; Mills, S. G.; Van Riper, G.; McCauley, E.; Egger, L. A.; Kidambi, U.; Lyons, K.; Vincent, S.; Stearns, R.; Colletti, A.; Teffera, J.; Tong, S.; Fenyk-Melody, J.; Owens, K.; Levorse, D.; Kim, P.; Schmidt, J. A.; Mumford, R. A. The discovery of sulfonylated dipeptides as potent VLA-4 antagonists. Bioorg. Med. Chem. Lett. 2001, 11, 2709– 2713, DOI: 10.1016/S0960-894X(01)00544-3[Crossref], [PubMed], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnsVKmtbY%253D&md5=80df53cefe5c9295c4e76cc67072446bThe discovery of sulfonylated dipeptides as Potent VLA-4 antagonistsHagmann, W. K.; Durette, P. L.; Lanza, T.; Kevin, N. J.; de Laszlo, S. E.; Kopka, I. E.; Young, D.; Magriotis, P. A.; Li, B.; Lin, L. S.; Yang, G.; Kamenecka, T.; Chang, L. L.; Wilson, J.; MacCoss, M.; Mills, S. G.; Van Riper, G.; McCauley, E.; Egger, L. A.; Kidambi, U.; Lyons, K.; Vincent, S.; Stearns, R.; Colletti, A.; Teffera, J.; Tong, S.; Fenyk-Melody, J.; Owens, K.; Levorse, D.; Kim, P.; Schmidt, J. A.; Mumford, R. A.Bioorganic & Medicinal Chemistry Letters (2001), 11 (20), 2709-2713CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Directed screening of a carboxylic acid-contg. combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid mol. gave a sub-nanomolar inhibitor as a lead for medicinal chem. Preliminary metabolic studies led to the discovery of substituted biphenyl derivs. with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.
- 235Choudhary, A.; Raines, R. T. An evaluation of peptide-bond isosteres. ChemBioChem 2011, 12, 1801– 1807, DOI: 10.1002/cbic.201100272[Crossref], [PubMed], [CAS], Google Scholar235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXoslaqurs%253D&md5=fc2aecec1937ace752f82a8817cd670aAn evaluation of peptide-bond isosteresChoudhary, Amit; Raines, Ronald T.ChemBioChem (2011), 12 (12), 1801-1807CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Peptide-bond isosteres can enable a deep interrogation of the structure and function of a peptide or protein by amplifying or attenuating particular chem. properties. Here, the authors examine in detail the electronic, structural, and conformational attributes of 4 such isosteres (thioamides, esters, alkenes, and fluoroalkenes). In particular, the ability of these isosteres to partake in noncovalent interactions is compared with that of the peptide bond. The consequential perturbations provide a useful tool for chem. biologists to reveal new structure-function relations, and to endow peptides and proteins with desirable attributes.
- 236Thorarensen, A.; Wakefield, B. D.; Romero, D. L.; Marotti, K. R.; Sweeney, M. T.; Zurenko, G. E.; Rohrer, D. C.; Han, F.; Bryant, G. L., Jr. Preparation of novel anthranilic acids as antibacterial agents. extensive evaluation of alternative amide bioisosteres connecting the A- and the B-rings. Bioorg. Med. Chem. Lett. 2007, 17, 2823– 2827, DOI: 10.1016/j.bmcl.2007.02.055[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkslOqu7c%253D&md5=cc2ae8ed70d31a8b136387e558344ea6Preparation of novel anthranilic acids as antibacterial agents. Extensive evaluation of alternative amide bioisosteres connecting the A- and the B-ringsThorarensen, Atli; Wakefield, Brian D.; Romero, Donna L.; Marotti, Keith R.; Sweeney, Michael T.; Zurenko, Gary E.; Rohrer, Douglas C.; Han, Fusen; Bryant, Garold L.Bioorganic & Medicinal Chemistry Letters (2007), 17 (10), 2823-2827CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)The identification of an anthranilic acid lead and the optimization resulting in the advanced lead I was recently described. In this report, the prepn. of several selected amide bioisosteres connecting the two benzene rings are described. The E-alkene provided a rigid analog with equal potency to the corresponding amide. This indicates that the amide is not a recognition element and rather acts as an appropriate spatial linker of the two important aryl rings. The work here clearly demonstrates that the amide linker can be replaced with several functionalities without significant deterioration in the MIC activity.
- 237Volonterio, A.; Bravo, P.; Zanda, M. Synthesis of partially modified retro and retroinverso ψ[NHCH(CF3)]-peptides. Org. Lett. 2000, 2, 1827– 1830, DOI: 10.1021/ol005876p[ACS Full Text], [CAS], Google Scholar237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXjsF2qt7o%253D&md5=bde723de92b56d7bbfbe2912ad5209b0Synthesis of Partially Modified Retro and Retroinverso ψ[NHCH(CF3)]-PeptidesVolonterio, Alessandro; Bravo, Pierfrancesco; Zanda, MatteoOrganic Letters (2000), 2 (13), 1827-1830CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)Asym. conjugate addns. of chiral α-amino esters to chiral 4-trifluoromethyl Michael-acceptors were exploited to prep. a small library of enantiomerically pure partially modified retropeptides having a ψ[NHCH(CF3)] unit as a possible mimic of the classical ψ(NHCO) retropeptide unit. Yields were nearly quant., and the stereoselectivity, which is controlled mainly by the N nucleophile, was progressively higher with increasing the steric bulk of the α-amino ester side-chain.
- 238Sani, M.; Volonterio, A.; Zanda, M. The trifluoroethylamine function as peptide bond replacement. ChemMedChem 2007, 2, 1693– 1700, DOI: 10.1002/cmdc.200700156[Crossref], [PubMed], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXltlWlt7c%253D&md5=f319f5ec15482837b159ae6776302717The trifluoroethylamine function as peptide bond replacementSani, Monica; Volonterio, Alessandro; Zanda, MatteoChemMedChem (2007), 2 (12), 1693-1700CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Synthesis of peptidomimetics contg. a stereogenic trifluoroethylamine group in place of the peptide bond is discussed. Peptidomimetics contg. the trifluoroethylamine group in place of amide group have been found to be highly potent and metabolically stable inhibitors of cathepsin K.
- 239Zanda, M. Trifluoromethyl group: an effective xenobiotic function for peptide backbone modification. New J. Chem. 2004, 28, 1401– 1411, DOI: 10.1039/b405955g[Crossref], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVGqur3P&md5=7f40c026008b7e521e5a8d47cdc6c36cTrifluoromethyl group: an effective xenobiotic function for peptide backbone modificationZanda, MatteoNew Journal of Chemistry (2004), 28 (12), 1401-1411CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)A review. Peptides modified with fluoroalkyl functions in key backbone positions have been scarcely studied so far. Thus, little is known about their synthesis, their structural and physico-chem. properties, and their biol. features. Interest in this field of research led to the development of stereocontrolled synthetic protocols, both in soln. and in the solid phase, for many different fluoroalkyl peptidomimetics, i.e., bis-trifluoromethyl (Tfm) analogs of Pepstatin A, which are nanomolar and selective inhibitors of the protozoal aspartyl protease Plasmepsin II; Tfm-malic peptidomimetics that are micromolar inhibitors of some matrix metalloproteinases; partially modified retro (PMR) and retro-inverso (PMRI) ψ[CH(CF3)NH] peptides with a strong proclivity to assume turn-like conformations; ψ[CH(CF3)NH] peptide mimics having a great potential as hybrids between natural peptides and hydrolytic transition state analogs; PMR peptides incorporating a trifluoroalanine surrogate. These novel classes of fluorinated peptide mimics are likely to represent just the tip of an iceberg formed by new peptidomimetic structures with unique biomedicinal and pharmaceutical properties.
- 240Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L. T.; Falgueyret, J. P.; Kimmel, D. B.; Lamontagne, S.; Leger, S.; LeRiche, T.; Li, C. S.; Masse, F.; McKay, D. J.; Nicoll-Griffith, D. A.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau, D.; Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Therien, M.; Truong, V. L.; Venuti, M. C.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 2008, 18, 923– 928, DOI: 10.1016/j.bmcl.2007.12.047[Crossref], [PubMed], [CAS], Google Scholar240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFWktro%253D&md5=e432a420a3ec99c784117750b9bbeda8The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin KGauthier, Jacques Yves; Chauret, Nathalie; Cromlish, Wanda; Desmarais, Sylvie; Duong, Le T.; Falgueyret, Jean-Pierre; Kimmel, Donald B.; Lamontagne, Sonia; Leger, Serge; LeRiche, Tammy; Li, Chun Sing; Masse, Frederic; McKay, Daniel J.; Nicoll-Griffith, Deborah A.; Oballa, Renata M.; Palmer, James T.; Percival, M. David; Riendeau, Denis; Robichaud, Joel; Rodan, Gideon A.; Rodan, Sevgi B.; Seto, Carmai; Therien, Michel; Truong, Vouy-Linh; Venuti, Michael C.; Wesolowski, Gregg; Young, Robert N.; Zamboni, Robert; Black, W. CameronBioorganic & Medicinal Chemistry Letters (2008), 18 (3), 923-928CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclin. species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.
- 241Grabowskal, U.; Chambers, T. J.; Shiroo, M. Recent developments in cathepsin K inhibitor design. Curr. Opin. Drug Discovery Dev. 2005, 8, 619– 630[PubMed], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MvovVGquw%253D%253D&md5=5ebd36480debe8b08eab9c536fc70470Recent developments in cathepsin K inhibitor designGrabowskal Urszula; Chambers Timothy J; Shiroo MasahiroCurrent opinion in drug discovery & development (2005), 8 (5), 619-30 ISSN:1367-6733.Cathepsin K is abundantly and selectively expressed in osteoclasts where it plays a critical role in bone degradation. Cathepsin K inhibitors are the first antiresorptive agents that prevent bone loss while allowing bone formation to continue, thereby enhancing the quality and ultimately the strength of bone. The development of cathepsin K inhibitors requires appropriate cell-based assays and animal models. Advances in reversible cathepsin K inhibitor design from January 2004 are reviewed herein.
- 242Falgueyret, J. P.; Desmarais, S.; Oballa, R.; Black, W. C.; Cromlish, W.; Khougaz, K.; Lamontagne, S.; Masse, F.; Riendeau, D.; Toulmond, S.; Percival, M. D. Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. J. Med. Chem. 2005, 48, 7535– 7543, DOI: 10.1021/jm0504961[ACS Full Text], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFKgsLbE&md5=9522026bb34984bc66b462b2e95fcbb0Lysosomotropism of Basic Cathepsin K Inhibitors Contributes to Increased Cellular Potencies against Off-Target Cathepsins and Reduced Functional SelectivityFalgueyret, Jean-Pierre; Desmarais, Sylvie; Oballa, Renata; Black, W. Cameron; Cromlish, Wanda; Khougaz, Karine; Lamontagne, Sonia; Masse, Frederic; Riendeau, Denis; Toulmond, Sylvie; Percival, M. DavidJournal of Medicinal Chemistry (2005), 48 (24), 7535-7543CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The lysosomal cysteine protease cathepsin K is a target for osteoporosis therapy. The aryl-piperazine-contg. cathepsin K inhibitor CRA-013783/L-006235 (1) displays greater than 4000-fold selectivity against the lysosomal/endosomal antitargets cathepsin B, L, and S. However, 1 and other aryl-piperazine-contg. analogs, including balicatib (10), are ∼10-100-fold more potent in cell-based enzyme occupancy assays than against each purified enzyme. This phenomenon arises from their basic, lipophilic nature, which results in lysosomal trapping. Consistent with its lysosomotropic nature, 1 accumulates in cells and in rat tissues of high lysosome content. In contrast, nonbasic aryl-morpholino-contg. analogs do not exhibit lysosomotropic properties. Increased off-target activities of basic cathepsin K inhibitors were obsd. in a cell-based cathepsin S antigen presentation assay. No potency increases of basic inhibitors in a functional cathepsin K bone resorption whole cell assay were detected. Therefore, basic cathepsin K inhibitors, such as 1, suffer from reduced functional selectivities compared to those predicted using purified enzyme assays.
- 243Li, C. S.; Deschenes, D.; Desmarais, S.; Falgueyret, J. P.; Gauthier, J. Y.; Kimmel, D. B.; Leger, S.; Masse, F.; McGrath, M. E.; McKay, D. J.; Percival, M. D.; Riendeau, D.; Rodan, S. B.; Therien, M.; Truong, V. L.; Wesolowski, G.; Zamboni, R.; Black, W. C. Identification of a potent and selective non-basic cathepsin K inhibitor. Bioorg. Med. Chem. Lett. 2006, 16, 1985– 1989, DOI: 10.1016/j.bmcl.2005.12.071[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhvVyqs74%253D&md5=e63e471204893774e5a617993ed9be18Identification of a potent and selective non-basic cathepsin K inhibitorLi, Chun Sing; Deschenes, Denis; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Gauthier, Jacques Yves; Kimmel, Donald. B.; Leger, Serge; Masse, Frederic; McGrath, Mary E.; McKay, Daniel J.; Percival, M. David; Riendeau, Denis; Rodan, Sevgi B.; Therien, Michel; Truong, Vouy-Linh; Wesolowski, Gregg; Zamboni, Robert; Black, W. CameronBioorganic & Medicinal Chemistry Letters (2006), 16 (7), 1985-1989CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of L-873724 (I) as a potent and selective non-basic cathepsin K inhibitor. This compd. showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The vols. of distribution close to unity were consistent with this compd. not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.
- 244Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falgueyret, J. P.; Leger, S.; Li, C. S.; Masse, F.; McKay, D. J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou, N.; Zamboni, R. Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2005, 15, 4741– 4744, DOI: 10.1016/j.bmcl.2005.07.071[Crossref], [PubMed], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVanu7%252FE&md5=c2ffc9bde9fbee7bb432d3c2485cfc62Trifluoroethylamines as amide isosteres in inhibitors of cathepsin KBlack, W. Cameron; Bayly, Christopher I.; Davis, Dana E.; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Leger, Serge; Li, Chun Sing; Masse, Frederic; McKay, Daniel J.; Palmer, James T.; Percival, M. David; Robichaud, Joel; Tsou, Nancy; Zamboni, RobertBioorganic & Medicinal Chemistry Letters (2005), 15 (21), 4741-4744CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The nonbasic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compds. are 10- to 20-fold more potent than the corresponding amide derivs. Compd. (I) is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.
- 245Mullard, A. Merck &Co. drops osteoporosis drug odanacatib. Nat. Rev. Drug Discovery 2016, 15, 669, DOI: 10.1038/nrd.2016.207[Crossref], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFymtL3M&md5=596d89f78b8396f0193a4ecfaf6b50bdMerck & Co. drops osteoporosis drug odanacatibMullard, AsherNature Reviews Drug Discovery (2016), 15 (10), 669CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A discussion of the osteoporosis drug odanacatib.
- 246Butler, C. R.; Ogilvie, K.; Martinez-Alsina, L.; Barreiro, G.; Beck, E. M.; Nolan, C. E.; Atchison, K.; Benvenuti, E.; Buzon, L.; Doran, S.; Gonzales, C.; Helal, C. J.; Hou, X.; Hsu, M. H.; Johnson, E. F.; Lapham, K.; Lanyon, L.; Parris, K.; O’Neill, B. T.; Riddell, D.; Robshaw, A.; Vajdos, F.; Brodney, M. A. Aminomethyl-derived beta secretase (BACE1) inhibitors: engaging Gly230 without an anilide functionality. J. Med. Chem. 2017, 60, 386– 402, DOI: 10.1021/acs.jmedchem.6b01451[ACS Full Text], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVWmsrzF&md5=d92838ac7f8a09921a560c3c9bb5d1afAminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide FunctionalityButler, Christopher R.; Ogilvie, Kevin; Martinez-Alsina, Luis; Barreiro, Gabriela; Beck, Elizabeth M.; Nolan, Charles E.; Atchison, Kevin; Benvenuti, Eric; Buzon, Leanne; Doran, Shawn; Gonzales, Cathleen; Helal, Christopher J.; Hou, Xinjun; Hsu, Mei-Hui; Johnson, Eric F.; Lapham, Kimberly; Lanyon, Lorraine; Parris, Kevin; O'Neill, Brian T.; Riddell, David; Robshaw, Ashley; Vajdos, Felix; Brodney, Michael A.Journal of Medicinal Chemistry (2017), 60 (1), 386-402CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and reveals a potential metabolic site leading to the formation of an aniline, a structural motif of potential safety concern. The authors report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogs with an excellent balance of ADME properties and potency, however potential drug-drug interactions (DDI) were predicted based on CYP2D6 affinities. Generation and anal. of key BACE1 and CYP2D6 crystal structures identified strategies to obviate the DDI liability, leading to compd. I which exhibits robust in vivo efficacy as a BACE1 inhibitor.
- 247Gaudette, F.; Raeppel, S.; Nguyen, H.; Beaulieu, N.; Beaulieu, C.; Dupont, I.; Macleod, A. R.; Besterman, J. M.; Vaisburg, A. Identification of potent and selective VEGFR receptor tyrosine kinase inhibitors having new amide isostere headgroups. Bioorg. Med. Chem. Lett. 2010, 20, 848– 852, DOI: 10.1016/j.bmcl.2009.12.099[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVGrurc%253D&md5=4ce25cdb55c553f33a7dab139ee0cc04Identification of potent and selective VEGFR receptor tyrosine kinase inhibitors having new amide isostere headgroupsGaudette, Frederic; Raeppel, Stephane; Nguyen, Hannah; Beaulieu, Normand; Beaulieu, Carole; Dupont, Isabelle; MacLeod, A. Robert; Besterman, Jeffrey M.; Vaisburg, ArkadiiBioorganic & Medicinal Chemistry Letters (2010), 20 (3), 848-852CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A novel series of malonamide-type dual VEGFR2/c-Met inhibitors in which one of the amide bonds was replaced by an amide isostere-a trifluoroethylamine unit, was designed, synthesized, and evaluated for their enzymic and cellular inhibition of VEGFR2 and c-Met enzymes. Optimization of these mol. entities resulted in identification of potent and selective inhibitors of VEGFR2 enzyme.
- 248Kim, K.; Kang, J.; Kim, S.; Choi, S.; Lim, S.; Im, C.; Yim, C. Synthesis and cytotoxicity of new aromatic ceramide analogs with alkylsulfonamido chains. Arch. Pharmacal Res. 2007, 30, 570– 580, DOI: 10.1007/BF02977651[Crossref], [PubMed], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXms1alsbg%253D&md5=0202cbb47f48f4032195837de3e193c8Synthesis and cytotoxicity of new aromatic ceramide analogs with alkylsulfonamido chainsKim, Kyoungwon; Kang, Joosung; Kim, Seungyong; Choi, Suhang; Lim, Sejin; Im, Chaeuk; Yim, ChulbuArchives of Pharmacal Research (2007), 30 (5), 570-580CODEN: APHRDQ; ISSN:0253-6269. (Pharmaceutical Society of Korea)A series of D-erythro ceramide analogs, N-(2S,3R,4E)-1, 3-dihydroxy-5-Ph-pent-4-en-2-yl alkyl sulfonamides, were synthesized and evaluated for their in vitro cytotoxic activities against five human tumor cell lines. The arom. sulfonamido ceramide analog I showed more potent cytotoxic activity than that of the B13, indicating that a sulfonamide group appears to serve as a bioisostere of an amide in drug design. Variations in the alkyl sulfonyl chain length significantly influenced the cytotoxic activity of the sulfonamido ceramide analogs, but the introduction of a para halogen on the Ph ring of arom. ceramide analogs had no affect on the activity.
- 249Donelson, J. L.; Hodges-Loaiza, H. B.; Henriksen, B. S.; Hrycyna, C. A.; Gibbs, R. A. Solid-phase synthesis of prenylcysteine analogs. J. Org. Chem. 2009, 74, 2975– 2981, DOI: 10.1021/jo8021692[ACS Full Text], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjs1Gmur4%253D&md5=74cd6ddac16572a9dcb67214e46e6fb5Solid-phase synthesis of prenylcysteine analogsDonelson, James L.; Hodges-Loaiza, Heather B.; Henriksen, Brian S.; Hrycyna, Christine A.; Gibbs, Richard A.Journal of Organic Chemistry (2009), 74 (8), 2975-2981CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Prenylcysteine derivs. are of interest for a variety of different biol. reasons, including probing the CaaX protein processing pathway. A solid-phase synthesis protocol for the prepn. of prenylcysteines using 2-chlorotrityl chloride resin as a solid support has been developed. A series of novel amide-modified farnesylcysteine analogs were synthesized in both high purity and yield under mild conditions. The farnesylcysteine analogs were evaluated using human isoprenylcysteine carboxyl methyltransferase as a biol. target, and several new inhibitors, one with significantly enhanced potency, were identified.
- 250Majmudar, J. D.; Hahne, K.; Hrycyna, C. A.; Gibbs, R. A. Probing the isoprenylcysteine carboxyl methyltransferase (Icmt) binding pocket: sulfonamide modified farnesyl cysteine (SMFC) analogs as Icmt inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 2616– 2620, DOI: 10.1016/j.bmcl.2011.01.078[Crossref], [PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltFKisbs%253D&md5=6d6a7272c83c936d4d99b0b88b134dbbProbing the isoprenylcysteine carboxyl methyltransferase (Icmt) binding pocket: Sulfonamide modified farnesyl cysteine (SMFC) analogs as Icmt inhibitorsMajmudar, Jaimeen D.; Hahne, Kalub; Hrycyna, Christine A.; Gibbs, Richard A.Bioorganic & Medicinal Chemistry Letters (2011), 21 (9), 2616-2620CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Human isoprenylcysteine carboxyl methyltransferase (hIcmt) is a promising anticancer target as it is important for the post-translational modification of oncogenic Ras proteins. We herein report the synthesis and biochem. activity of 41 farnesyl-cysteine based analogs vs. hIcmt. We have demonstrated that the amide linkage of a hIcmt substrate can be replaced by a sulfonamide bond to achieve hIcmt inhibition. The most potent sulfonamide-modified farnesyl cysteine analog was 6ag with an IC50 of 8.8 ± 0.5 μM for hIcmt.
- 251Koehn, F. E.; Carter, G. T. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discovery 2005, 4, 206– 220, DOI: 10.1038/nrd1657[Crossref], [PubMed], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhslSnsrg%253D&md5=ce80052abaa76430220ee5981138053eThe evolving role of natural products in drug discoveryKoehn, Frank E.; Carter, Guy T.Nature Reviews Drug Discovery (2005), 4 (3), 206-220CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Natural products and their derivs. have historically been invaluable as a source of therapeutic agents. However, in the past decade, research into natural products in the pharmaceutical industry has declined, owing to issues such as the lack of compatibility of traditional natural-product ext. libraries with high-throughput screening. However, as discussed in this review, recent technol. advances that help to address these issues, coupled with unrealized expectations from current lead-generation strategies, have led to a renewed interest in natural products in drug discovery.
- 252Ferreira, A. K.; Tavares, M. T.; Pasqualoto, K. F.; de Azevedo, R. A.; Teixeira, S. F.; Ferreira-Junior, W. A.; Bertin, A. M.; de-Sa-Junior, P. L.; Barbuto, J. A.; Figueiredo, C. R.; Cury, Y.; Damiao, M. C.; Parise-Filho, R. RPF151, a novel capsaicin-like analogue: in vitro studies and in vivo preclinical antitumor evaluation in a breast cancer model. Tumor Biol. 2015, 36, 7251– 7267, DOI: 10.1007/s13277-015-3441-z[Crossref], [CAS], Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVyqs73E&md5=fb6c7a340e8127027f797fd16d425c69RPF151, a novel capsaicin-like analogue: in vitro studies and in vivo preclinical antitumor evaluation in a breast cancer modelFerreira, Adilson Kleber; Tavares, Mauricio Temotheo; Pasqualoto, Kerly Fernanda Mesquita; de Azevedo, Ricardo Alexandre; Teixeira, Sarah Fernandes; Ferreira-Junior, Wilson Alves; Bertin, Ariane Matiello; de-Sa-Junior, Paulo Luiz; Barbuto, Jose Alexandre Marzagao; Figueiredo, Carlos Rogerio; Cury, Yara; Damiao, Mariana Celestina Frojuello Costa Bernstorff; Parise-Filho, RobertoTumor Biology (2015), 36 (9), 7251-7267CODEN: TUMBEA; ISSN:1010-4283. (Springer)Capsaicin, the primary pungent component of the chili pepper, has antitumor activity. Herein, we describe the activity of RPF151, an alkyl sulfonamide analog of capsaicin, against MDA-MB-231 breast cancer cells. RPF151 was synthesized, and mol. modeling was used to compare capsaicin and RPF151. Cytotoxicity of RPF151 on MDA-MB-231 was also evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5diphenyltetrazolium bromide (MTT) assay. Cell cycle anal., by flow cytometry, and Western blot anal. of cycle-related proteins were used to evaluate the antiproliferative mechanisms. Apoptosis was evaluated by phosphatidyl-serine externalization, cleavage of Ac-YVAD-AMC, and Bcl-2 expression. The prodn. of reactive oxygen species was evaluated by flow cytometry. RPF151 in vivo antitumor effects were investigated in murine MDA-MB-231 model. This study shows that RPF151 downregulated p21 and cyclins A, D1, and D3, leading to S-phase arrest and apoptosis. Although RPF151 has induced the activation of TRPV-1 and TRAIL-R1/DR4 and TRAIL-2/DR5 on the surface of MDA-MB-231 cells, its in vivo antitumor activity was TRPV-1-independent, thus suggesting that RPF151 should not have the same pungency-based limitation of capsaicin. In silico anal. corroborated the biol. findings, showing that RPF151 has physicochem. improvements over capsaicin. Overall, the activity of RPF151 against MDA-MB-231 and its lower pungency suggest that it may have a relevant role in cancer therapy.
- 253de-Sa-Junior, P. L.; Pasqualoto, K. F.; Ferreira, A. K.; Tavares, M. T.; Damiao, M. C.; de Azevedo, R. A.; Camara, D. A.; Pereira, A.; de Souza, D. M.; Parise Filho, R. RPF101, a new capsaicin-like analogue, disrupts the microtubule network accompanied by arrest in the G2/M phase, inducing apoptosis and mitotic catastrophe in the MCF-7 breast cancer cells. Toxicol. Appl. Pharmacol. 2013, 266, 385– 398, DOI: 10.1016/j.taap.2012.11.029[Crossref], [PubMed], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXos1Sqsw%253D%253D&md5=d79537f1bb7ea7762db7f967731e5c67RPF101, a new capsaicin-like analogue, disrupts the microtubule network accompanied by arrest in the G2/M phase, inducing apoptosis and mitotic catastrophe in the MCF-7 breast cancer cellsde-Sa-Junior, Paulo Luiz; Pasqualoto, Kerly Fernanda Mesquita; Ferreira, Adilson Kleber; Tavares, Mauricio Temotheo; Damiao, Mariana Celestina Frojuello Costa Bernstorff; de Azevedo, Ricardo Alexandre; Camara, Diana Aparecida Dias; Pereira, Alexandre; Madeiro de Souza, Dener; Parise Filho, RobertoToxicology and Applied Pharmacology (2013), 266 (3), 385-398CODEN: TXAPA9; ISSN:0041-008X. (Elsevier Inc.)Breast cancer is the world's leading cause of death among women. This situation imposes an urgent development of more selective and less toxic agents. The use of natural mol. fingerprints as sources for new bioactive chem. entities has proven to be a quite promising and efficient method. Capsaicin, which is the primary pungent compd. in red peppers, was reported to selectively inhibit the growth of a variety tumor cell lines. Here, we report for the first time a novel synthetic capsaicin-like analog, RPF101, which presents a high antitumor activity on MCF-7 cell line, inducing arrest of the cell cycle at the G2/M phase through a disruption of the microtubule network. Furthermore, it causes cellular morphol. changes characteristic of apoptosis and a decrease of Δψm. Mol. modeling studies corroborated the biol. findings and suggested that RPF101, besides being a more reactive mol. towards its target, may also present a better pharmacokinetic profile than capsaicin. All these findings support the fact that RPF101 is a promising anticancer agent.
- 254Choy, N.; Choi, H.-I.; Jung, W. H.; Kim, C. R.; Yoon, H.; Kim, S. C.; Lee, T. G.; Koh, J. S. Synthesis of irreversible HIV-1 protease inhibitors containing sulfonamide and sulfone as amide bond isosteres. Bioorg. Med. Chem. Lett. 1997, 7, 2635– 2638, DOI: 10.1016/S0960-894X(97)10054-3[Crossref], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXnt1WktL8%253D&md5=426c15ab9072ba5c2499707c42e84127Synthesis of irreversible HIV-1 protease inhibitors containing sulfonamide and sulfone as amide bond isosteresChoy, Nakyen; Choi, Ho-il; Jung, Won Hee; Kim, Chung Ryeol; Yoon, Heungsik; Kim, Sung Chun; Lee, Tae Gyu; Koh, Jong SungBioorganic & Medicinal Chemistry Letters (1997), 7 (20), 2635-2638CODEN: BMCLE8; ISSN:0960-894X. (Elsevier)Novel irreversible HIV-1 protease inhibitors contg. sulfonamide and sulfone as amide bond isosteres were designed, synthesized, and kinetically characterized. A representative compd. (I) displayed rapid, time-dependent inactivation of HIV-1 protease and high potency in cell culture with IC50 of 6.6 nM.
- 255Shu, B.; Gong, P. Structural basis of viral RNA-dependent RNA polymerase catalysis and translocation. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, E4005– E4014, DOI: 10.1073/pnas.1602591113[Crossref], [PubMed], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFentrnO&md5=c06d8ebd751beab84fd77603cb82000dStructural basis of viral RNA-dependent RNA polymerase catalysis and translocationShu, Bo; Gong, PengProceedings of the National Academy of Sciences of the United States of America (2016), 113 (28), E4005-E4014CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Viral RNA-dependent RNA polymerases (RdRPs) play essential roles in viral genome replication and transcription. We previously reported several structural states of the poliovirus RdRP nucleotide addn. cycle (NAC) that revealed a unique palm domain-based active site closure mechanism and proposed a six-state NAC model including a hypothetical state representing translocation intermediates. Using the RdRP from another human enterovirus, enterovirus 71, here we report seven RdRP elongation complex structures derived from a crystal lattice that allows three NAC events. These structures suggested a key order of events in initial NTP binding and NTP-induced active site closure and revealed a bona fide translocation intermediate featuring asym. movement of the template-product duplex. Our work provides essential missing links in understanding NTP recognition and translocation mechanisms in viral RdRPs and emphasizes the uniqueness of the viral RdRPs compared with other processive polymerases.
- 256Venkataraman, S.; Prasad, B.; Selvarajan, R. RNA dependent RNA Polymerases: insights from structure, function and evolution. Viruses 2018, 10, 76, DOI: 10.3390/v10020076[Crossref], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlOns7fM&md5=c319809dde32ed7bef696dd77566920dRNA dependent RNA polymerases: insights from structure, function and evolutionVenkataraman, Sangita; Prasad, Burra V. L. S.; Selvarajan, RamasamyViruses (2018), 10 (2), 76/1-76/23CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)RNA dependent RNA polymerase (RdRp) is one of the most versatile enzymes of RNA viruses that is indispensable for replicating the genome as well as for carrying out transcription. The core structural features of RdRps are conserved, despite the divergence in their sequences. The structure of RdRp resembles that of a cupped right hand and consists of fingers, palm and thumb subdomains. The catalysis involves the participation of conserved aspartates and divalent metal ions. Complexes of RdRps with substrates, inhibitors and metal ions provide a comprehensive view of their functional mechanism and offer valuable insights regarding the development of antivirals. In this article, we provide an overview of the structural aspects of RdRps and their complexes from the Group III, IV and V viruses and their structure-based phylogeny.
- 257Abdurakhmanov, E.; Oie Solbak, S.; Danielson, U. H. Biophysical mode-of-action and selectivity analysis of allosteric inhibitors of hepatitis C virus (HCV) polymerase. Viruses 2017, 9, 151, DOI: 10.3390/v9060151[Crossref], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVertbbF&md5=33824302ecfbe96c36b990b79d587e24Biophysical mode-of-action and selectivity analysis of allosteric inhibitors of hepatitis C virus (HCV) polymeraseAbdurakhmanov, Eldar; Solbak, Sara Oie; Danielson, U. HelenaViruses (2017), 9 (6), 151/1-151/20CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)Allosteric inhibitors of hepatitis C virus (HCV) non-structural protein 5B (NS5B) polymerase are effective for treatment of genotype 1, although their mode of action and potential to inhibit other isolates and genotypes are not well established. We have used biophys. techniques and a novel biosensor-based real-time polymerase assay to investigate the mode-of-action and selectivity of four inhibitors against enzyme from genotypes 1b (BK and Con1) and 3a. Two thumb inhibitors (lomibuvir and filibuvir) interacted with all three NS5B variants, although the affinities for the 3a enzyme were low. Of the two tested palm inhibitors (dasabuvir and nesbuvir), only dasabuvir interacted with the 1b variant, and nesbuvir interacted with NS5B 3a. Lomibuvir, filibuvir and dasabuvir stabilized the structure of the two 1b variants, but not the 3a enzyme. The thumb compds. interfered with the interaction between the enzyme and RNA and blocked the transition from initiation to elongation. The two allosteric inhibitor types have different inhibition mechanisms. Sequence and structure anal. revealed differences in the binding sites for 1b and 3a variants, explaining the poor effect against genotype 3a NS5B. The indirect mode-of-action needs to be considered when designing allosteric compds. The current approach provides an efficient strategy for identifying and optimizing allosteric inhibitors targeting HCV genotype 3a.
- 258Kati, W.; Koev, G.; Irvin, M.; Beyer, J.; Liu, Y.; Krishnan, P.; Reisch, T.; Mondal, R.; Wagner, R.; Molla, A.; Maring, C.; Collins, C. In vitro activity and resistance profile of dasabuvir, a nonnucleoside hepatitis C virus polymerase inhibitor. Antimicrob. Agents Chemother. 2015, 59, 1505– 1511, DOI: 10.1128/AAC.04619-14[Crossref], [PubMed], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtFais7Y%253D&md5=90e37367cb8769886a834675a9f237e9In Vitro Activity and resistance profile of dasabuvir, a nonnucleoside hepatitis C virus polymerase inhibitorKati, Warren; Koev, Gennadiy; Irvin, Michelle; Beyer, Jill; Liu, Yaya; Krishnan, Preethi; Reisch, Thomas; Mondal, Rubina; Wagner, Rolf; Molla, Akhteruzzaman; Maring, Clarence; Collins, ChristineAntimicrobial Agents and Chemotherapy (2015), 59 (3), 1505-1511/1-1505-1511/7, 7 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Dasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clin. isolates, with 50% inhibitory concn. (IC50) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concn. (EC50) values of 7.7 and 1.8 nM, resp., with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clin. isolates from treatment-naive patients, with EC50s ranging between 0.15 and 8.57 nM. Maintenance of replicon-contg. cells in medium contg. dasabuvir at concns. 10-fold or 100-fold greater than the EC50 resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections.
- 259Pierra Rouviere, C.; Amador, A.; Badaroux, E.; Convard, T.; Da Costa, D.; Dukhan, D.; Griffe, L.; Griffon, J. F.; LaColla, M.; Leroy, F.; Liuzzi, M.; Loi, A. G.; McCarville, J.; Mascia, V.; Milhau, J.; Onidi, L.; Paparin, J. L.; Rahali, R.; Sais, E.; Seifer, M.; Surleraux, D.; Standring, D.; Dousson, C. Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase. Bioorg. Med. Chem. Lett. 2016, 26, 4536– 4541, DOI: 10.1016/j.bmcl.2016.01.042[Crossref], [PubMed], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhtlalt7zL&md5=8249681b3bba0b04b03da0b11aada4a7Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerasePierra Rouviere, Claire; Amador, Agnes; Badaroux, Eric; Convard, Thierry; Da Costa, Daniel; Dukhan, David; Griffe, Ludovic; Griffon, Jean-Francois; La Colla, Massimiliano; Leroy, Frederic; Liuzzi, Michel; Loi, Anna Giulia; McCarville, Joe; Mascia, Valeria; Milhau, Julien; Onidi, Loredana; Paparin, Jean-Laurent; Rahali, Rachid; Sais, Efisio; Seifer, Maria; Surleraux, Dominique; Standring, David; Dousson, CyrilBioorganic & Medicinal Chemistry Letters (2016), 26 (18), 4536-4541CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equiv. in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by x-ray co-crystn. study.
- 260Rochon, K.; Proteau-Gagne, A.; Bourassa, P.; Nadon, J. F.; Cote, J.; Bournival, V.; Gobeil, F., Jr.; Guerin, B.; Dory, Y. L.; Gendron, L. Preparation and evaluation at the delta opioid receptor of a series of linear leu-enkephalin analogues obtained by systematic replacement of the amides. ACS Chem. Neurosci. 2013, 4, 1204– 1216, DOI: 10.1021/cn4000583[ACS Full Text], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntVCqu7s%253D&md5=8f417f41d4c48bd3aa3a4d4a52604ad4Preparation and Evaluation at the Delta Opioid Receptor of a Series of Linear Leu-Enkephalin Analogues Obtained by Systematic Replacement of the AmidesRochon, Kristina; Proteau-Gagne, Arnaud; Bourassa, Philippe; Nadon, Jean-Francois; Cote, Jerome; Bournival, Veronique; Gobeil, Fernand; Guerin, Brigitte; Dory, Yves L.; Gendron, LouisACS Chemical Neuroscience (2013), 4 (8), 1204-1216CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Leu-enkephalin analogs, in which the amide bonds were sequentially and systematically replaced either by ester or N-Me amide bonds, were prepd. using classical org. chem. as well as solid-phase peptide synthesis (SPPS). The peptidomimetics were characterized using competition binding, ERK1/2 phosphorylation, receptor internalization, and contractility assays to evaluate their pharmacol. profile over the delta opioid receptor (DOPr). The lipophilicity (LogD7.4) and plasma stability of the active analogs were also measured. The results here revealed that the last amide bond can be successfully replaced by either an ester or an N-Me amide bond without significantly decreasing the biol. activity of the corresponding analogs when compared to Leu-enkephalin. The peptidomimetics with an N-Me amide function between residues Phe and Leu were found to be more lipophilic and more stable than Leu-enkephalin. Findings from the present study further revealed that the hydrogen-bond donor properties of the fourth amide of Leu-enkephalin are not important for its biol. activity on DOPr. In addn., the results showed that the systematic replacement of amide bonds by isosteric functions represents an efficient way to design and synthesize novel peptide analogs with enhanced stability. In conclusion, the authors suggest that such a strategy can also be useful to study the biol. roles of amide bonds.
- 261Hann, M. M.; Sammes, P. G.; Kennewell, P. D.; Taylor, J. B. On double bond isosters of the peptide bond; an enkephalin analogue. J. Chem. Soc., Chem. Commun. 1980, 234– 235, DOI: 10.1039/c39800000234[Crossref], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXlsFSlsb0%253D&md5=7defca8db5fbe3f588428a99382b72aaOn double bond isosteres of the peptide bond; an enkephalin analogHann, Michael M.; Sammes, Peter G.; Kennewell, Peter D.; Taylor, John B.Journal of the Chemical Society, Chemical Communications (1980), (5), 234-5CODEN: JCCCAT; ISSN:0022-4936.A route to peptide analogs incorporating a trans C-C double bond in place of an amide bond is described and illustrated by the prepn. of leucine enkephalin analog I. The opiate activity of I was assessed; I had an IC50 of 600nM against [3H]naloxone bound to rat brain homogenates at 30°.
- 262Hann, M. M.; Sammes, P. G.; Kennewell, P. D.; Taylor, J. B. On the double bond isostere of the peptide bond: preparation of an enkephalin analogue. J. Chem. Soc., Perkin Trans. 1 1982, 307– 314, DOI: 10.1039/p19820000307[Crossref], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XksFKhs7c%253D&md5=f2e6ec3a9f39f4a8cc32de8d4a4fdc22On the double bond isostere of the peptide bond: preparation of an enkephalin analogHann, Michael M.; Sammes, Peter G.; Kennewell, Peter D.; Taylor, John B.Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1982), (1), 307-14CODEN: JCPRB4; ISSN:0300-922X.The prepn. is described of a dipeptide analog in which a C:C bond replaces the normal amide bond. Ether I (R = CHO), prepd. by redn. of I (R = CO2Me), underwent Wittig reaction with Ph3P+CH2C≡CSiMe3 Br- to give 76% I [R = (E)-CH:CHC≡CSiMe3], which underwent desilylation and oxidn. to give 75% I [R = (E)-CH:CHCH2CO2H] (II). II was condensed with H-Gly-Phe-Leu-OMe to give 68% I [R = (E)-CH:CHCH2CO-Gly-Phe-Leu-OMe], which was deprotected to give enkephalin analog III. III exhibited a biol. activity similar to that of enkephalin. The significance of the isosteric replacement of the amide group is discussed.
- 263Wipf, P.; Henninger, T. C.; Geib, S. J. Methyl- and (trifluoromethyl)alkene peptide isosteres: synthesis and evaluation of their potential as β-turn promoters and peptide mimetics. J. Org. Chem. 1998, 63, 6088– 6089, DOI: 10.1021/jo981057v[ACS Full Text], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXltFejsLg%253D&md5=a1d8b91ced24c2d1871dd041115a6b52Methyl- and (Trifluoromethyl)alkene Peptide Isosteres: Synthesis and Evaluation of Their Potential as β-Turn Promoters and Peptide MimeticsWipf, Peter; Henninger, Todd C.; Geib, Steven J.Journal of Organic Chemistry (1998), 63 (18), 6088-6089CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Enantioselective synthetic approaches were devised for L-ala-D-Ala (or enantiomeric) dipeptide alkene isostere sequences that, for the first time, included the prepn. of a (trifluoromethyl)alkene isostere. An X-ray study established that methyl- and trifluoromethyl-substituted alkenes provide conformationally considerably more highly preorganized backbone-rigidified peptide mimetics than the parent disubstituted alkenes.
- 264Donner, P.; Randolph, J. T.; Huang, P.; Wagner, R.; Maring, C.; Lim, B. H.; Colletti, L.; Liu, Y.; Mondal, R.; Beyer, J.; Koev, G.; Marsh, K.; Beno, D.; Longenecker, K.; Pilot-Matias, T.; Kati, W.; Molla, A.; Kempf, D. High potency improvements to weak aryl uracil HCV polymerase inhibitor leads. Bioorg. Med. Chem. Lett. 2013, 23, 4367– 4369, DOI: 10.1016/j.bmcl.2013.05.078[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpslGjurk%253D&md5=5bd3f614d5644d6b2f8ff963c090e9b1High potency improvements to weak aryl uracil HCV polymerase inhibitor leadsDonner, Pamela; Randolph, John T.; Huang, Peggy; Wagner, Rolf; Maring, Clarence; Lim, Ben Hock; Colletti, Lynn; Liu, Yaya; Mondal, Rubina; Beyer, Jill; Koev, Gennadiy; Marsh, Kennan; Beno, David; Longenecker, Kenton; Pilot-Matias, Tami; Kati, Warren; Molla, Akhter; Kempf, DaleBioorganic & Medicinal Chemistry Letters (2013), 23 (15), 4367-4369CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Described herein is the development of a potent non-nucleoside, small mol. inhibitor of genotype 1 HCV NS5B Polymerase. A 23 μM inhibitor that was active against HCV polymerase was further elaborated into a potent single-digit nanomolar inhibitor of HCV NS5B polymerase by addnl. manipulation of the R and R1 substituents. Subsequent modifications to improve phys. properties were made to achieve an acceptable pharmacokinetic profile.
- 265Randolph, J. T.; Krueger, A. C.; Donner, P. L.; Pratt, J. K.; Liu, D.; Motter, C. E.; Rockway, T. W.; Tufano, M. D.; Wagner, R.; Lim, H. B.; Beyer, J. M.; Mondal, R.; Panchal, N. S.; Colletti, L.; Liu, Y.; Koev, G.; Kati, W. M.; Hernandez, L. E.; Beno, D. W. A.; Longenecker, K. L.; Stewart, K. D.; Dumas, E. O.; Molla, A.; Maring, C. J. Synthesis and biological characterization of aryl uracil inhibitors of hepatitis C virus NS5B polymerase: discovery of ABT-072, a trans-stilbene analog with good oral bioavailability. J. Med. Chem. 2018, 61, 1153– 1163, DOI: 10.1021/acs.jmedchem.7b01630[ACS Full Text], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1GgurY%253D&md5=e5fe750b61c6fc317eeae03d1bea8955Synthesis and Biological Characterization of Aryl Uracil Inhibitors of Hepatitis C Virus NS5B Polymerase: Discovery of ABT-072, a trans-Stilbene Analog with Good Oral BioavailabilityRandolph, John T.; Krueger, A. Chris; Donner, Pamela L.; Pratt, John K.; Liu, Dachun; Motter, Christopher E.; Rockway, Todd W.; Tufano, Michael D.; Wagner, Rolf; Lim, Hock B.; Beyer, Jill M.; Mondal, Rubina; Panchal, Neeta S.; Colletti, Lynn; Liu, Yaya; Koev, Gennadiy; Kati, Warren M.; Hernandez, Lisa E.; Beno, David W. A.; Longenecker, Kenton L.; Stewart, Kent D.; Dumas, Emily O.; Molla, Akhteruzzaman; Maring, Clarence J.Journal of Medicinal Chemistry (2018), 61 (3), 1153-1163CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compd. was identified during a medicinal chem. effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compd. permeability and soly. and provided much better pharmacokinetic properties in preclin. species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clin. studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clin. study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virol. response at 24 wk after dosing (SVR24) in 10 of 11 patients who received treatment.
- 266Durham, P. L. Calcitonin gene-related peptide (CGRP) and migraine. Headache 2006, 46 (Suppl. 1), S3– S8, DOI: 10.1111/j.1526-4610.2006.00483.x[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28rgtlKhsQ%253D%253D&md5=0336b66327b4a1b82d7ea5b0dff485bfCalcitonin gene-related peptide (CGRP) and migraineDurham Paul LHeadache (2006), 46 Suppl 1 (), S3-8 ISSN:0017-8748.The neuropeptide calcitonin gene-related peptide (CGRP) has long been postulated to play an integral role in the pathophysiology of migraine. While clinical findings are consistent with such a role, the specific pathogenic mechanisms of CGRP in migraine have remained speculative until recently. Through advances in molecular neuroscience, the pathogenic mechanisms of CGRP in migraine have begun to be elucidated. This paper discusses the hypothesized role of CGRP in migraine and reviews recent findings on the molecular mechanisms of this neuropeptide in migraine pathophysiology. Studies in cultured trigeminal neurons demonstrate that CGRP is released from trigeminal ganglia cells, that CGRP transcription is increased under conditions mimicking neurogenic inflammation, that migraine pharmacotherapies can both reduce CGRP release and inhibit CGRP transcription, and that tumor necrosis factor-alpha (TNF-alpha), an endogenous inflammatory mediator implicated in migraine, can stimulate CGRP transcription. Together, the results suggest that, in migraine, activation of trigeminal nerves release CGRP and other peptides that cause the release of proinflammatory mediators. These mediators further increase CGRP synthesis and release over hours to days in correspondence with the 4- to 72-hour duration of a typical migraine episode. The increased CGRP synthesis and release might be mediated by activation of mitogen-activated protein kinase pathways, which, in turn, can be modulated by endogenous inflammatory substances such as TNF-alpha and affected by drugs such as sumatriptan.
- 267Russell, F. A.; King, R.; Smillie, S. J.; Kodji, X.; Brain, S. D. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol. Rev. 2014, 94, 1099– 1142, DOI: 10.1152/physrev.00034.2013[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFansbnI&md5=dabce66d0b7604444f8366056f1ba2fdCalcitonin gene-related peptide: physiology and pathophysiologyRussell, F. A.; King, R.; Smillie, S.-J.; Kodji, X.; Brain, S. D.Physiological Reviews (2014), 94 (4), 1099-1142CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)A review. Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiol. and pathol. conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biol., but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this mol.
- 268Stump, C. A.; Bell, I. M.; Bednar, R. A.; Bruno, J. G.; Fay, J. F.; Gallicchio, S. N.; Johnston, V. K.; Moore, E. L.; Mosser, S. D.; Quigley, A. G.; Salvatore, C. A.; Theberge, C. R.; Blair Zartman, C.; Zhang, X. F.; Kane, S. A.; Graham, S. L.; Vacca, J. P.; Williams, T. M. The discovery of highly potent CGRP receptor antagonists. Bioorg. Med. Chem. Lett. 2009, 19, 214– 217, DOI: 10.1016/j.bmcl.2008.10.106[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlvFKk&md5=ad4ac18cac6f692017e08a3f3e946937The discovery of highly potent CGRP receptor antagonistsStump, Craig A.; Bell, Ian M.; Bednar, Rodney A.; Bruno, Joseph G.; Fay, John F.; Gallicchio, Steven N.; Johnston, Victor K.; Moore, Eric L.; Mosser, Scott D.; Quigley, Amy G.; Salvatore, Christopher A.; Theberge, Cory R.; Blair Zartman, C.; Zhang, Xu-Fang; Kane, Stefanie A.; Graham, Samuel L.; Vacca, Joseph P.; Williams, Theresa M.Bioorganic & Medicinal Chemistry Letters (2009), 19 (1), 214-217CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP Ki = 40 pM). The closely related compd. 27 demonstrated good oral bioavailability in dog and rhesus.
- 269Kim, J. J.; Wood, M. R.; Stachel, S. J.; de Leon, P.; Nomland, A.; Stump, C. A.; McWherter, M. A.; Schirripa, K. M.; Moore, E. L.; Salvatore, C. A.; Selnick, H. G. (E)-Alkenes as replacements of amide bonds: development of novel and potent acyclic CGRP receptor antagonists. Bioorg. Med. Chem. Lett. 2014, 24, 258– 261, DOI: 10.1016/j.bmcl.2013.11.027[Crossref], [PubMed], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFOku73O&md5=bc08abb6a057601a35feeb3e937b61df(E)-Alkenes as replacements of amide bonds: Development of novel and potent acyclic CGRP receptor antagonistsKim, June J.; Wood, Michael R.; Stachel, Shawn J.; de Leon, Pablo; Nomland, Ashley; Stump, Craig A.; McWherter, Melody A.; Schirripa, Kathy M.; Moore, Eric L.; Salvatore, Christopher A.; Selnick, Harold G.Bioorganic & Medicinal Chemistry Letters (2014), 24 (1), 258-261CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compds. against CGRP-R with low susceptibility to P-gp mediated efflux.
- 270Larsen, S. D.; Hester, M. R.; Craig Ruble, J.; Kamilar, G. M.; Romero, D. L.; Wakefield, B.; Melchior, E. P.; Sweeney, M. T.; Marotti, K. R. Discovery and initial development of a novel class of antibacterials: inhibitors of Staphylococcus aureus transcription/translation. Bioorg. Med. Chem. Lett. 2006, 16, 6173– 6177, DOI: 10.1016/j.bmcl.2006.09.044[Crossref], [PubMed], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtF2jsr%252FF&md5=e10c4cc122a0c2cd03d662ec57a9d77bDiscovery and initial development of a novel class of antibacterials: Inhibitors of Staphylococcus aureus transcription/translationLarsen, Scott D.; Hester, Matthew R.; Ruble, J. Craig; Kamilar, Gregg M.; Romero, Donna L.; Wakefield, Brian; Melchior, Earline P.; Sweeney, Michael T.; Marotti, Keith R.Bioorganic & Medicinal Chemistry Letters (2006), 16 (24), 6173-6177CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)The novel bacterial transcription/translation (TT) inhibitor 1 was identified through a combination of high throughput screening and exploratory medicinal chem. Initial optimization of the anthranilic acid moiety and sulfonamide amine diversity was accomplished via 1- and two-dimensional soln. phase libraries, resulting in an improvement in the MIC of the lead from 64 to 8 μg/mL (compd. 4l). Subsequent modification of the central arom. ring and further refinement of the sulfonamide amines required the development of a solid phase route on Wang resin. The resulting libraries generated a no. of potent antibacterials with MICs of ≤1 μg/mL (e.g., 10b, 12, and 13). During the course of this work, it became apparent that the antibacterial activity of the series is not fully correlated with TT inhibition, suggesting that at least one addnl. mechanism of action is operative.
- 271Brouwer, A. J.; Elgersma, R. C.; Jagodzinska, M.; Rijkers, D. T.; Liskamp, R. M. Delayed fibril formation of amylin(20-29) by incorporation of alkene dipeptidosulfonamide isosteres obtained by solid phase olefin cross metathesis. Bioorg. Med. Chem. Lett. 2008, 18, 78– 84, DOI: 10.1016/j.bmcl.2007.11.009[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXis1WntA%253D%253D&md5=9c6209f003e27d3a764ae1ab50d7f5afDelayed fibril formation of amylin(20-29) by incorporation of alkene dipeptidosulfonamide isosteres obtained by solid phase olefin cross metathesisBrouwer, Arwin J.; Elgersma, Ronald C.; Jagodzinska, Monika; Rijkers, Dirk T. S.; Liskamp, Rob M. J.Bioorganic & Medicinal Chemistry Letters (2008), 18 (1), 78-84CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)The synthesis of a new peptidomimetic structure, the alkene dipeptidosulfonamide isostere, is described. The synthesis is based on a cross metathesis reaction between two allylic building blocks, both in soln. and on the solid phase. This method was also applicable to the solid phase synthesis of alkene dipeptide isosteres. Derivs. of amylin(20-29) contg. the alkene dipeptidosulfonamide isostere as well as the alkene dipeptide isostere were successfully synthesized using the solid phase cross metathesis method. Investigation of relations between structure and fibril formation of these amylin(20-29) derivs. showed retardation of fibril formation and altered secondary structures, compared to native amylin(20-29).
- 272Yamamoto, Y.; Kimachi, T.; Kanaoka, Y.; Kato, S.; Bessho, K.; Matsumoto, T.; Kusakabe, T.; Sugiura, Y. Synthesis and DNA binding properties of amide bond-modified analogues related to distamycin. Tetrahedron Lett. 1996, 37, 7801– 7804, DOI: 10.1016/0040-4039(96)01782-0[Crossref], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xms1Wlt7s%253D&md5=de211ec74437e3ba757142a6502beaf0Synthesis and DNA binding properties of amide bond-modified analogs related to distamycinYamamoto, Yasuo; Kimachi, Tetsutaro; Kanaoka, Yoshitomo; Kato, Satoshi; Bessho, Kiyoshi; Matsumoto, Takuyuki; Kusakabe, Tetsuya; Sugiura, YukioTetrahedron Letters (1996), 37 (43), 7801-7804CODEN: TELEAY; ISSN:0040-4039. (Elsevier)Novel nitro analogs of distamycin I (X = CH:CH, COCO) which have a trans olefin bond or an α-diketo moiety instead of an amide bond were synthesized. Their DNA binding properties studied by ethidium displacement assay and MPE footprinting expts. were also described.
- 273Arcamone, F.; Penco, S.; Orezzi, P.; Nicolella, V.; Pirelli, A. Structure and synthesis of distamycin A. Nature 1964, 203, 1064– 1065, DOI: 10.1038/2031064a0[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2cXkvVClsrk%253D&md5=e418caf3c06330e1dec898811dbb7cf3Structure and synthesis of distamycin AArcamone, F.; Penco, S.; Orezzi, P.; Nicolella, V.; Pirelli, AnnamariaNature (London, United Kingdom) (1964), 203 (4949), 1064-5CODEN: NATUAS; ISSN:0028-0836.An amorphous product (fraction A) was sepd. from distamycin by solvent fractionation and column chromatography on Al2O3. The basic antibiotic distamycin A (I) was obtained as the HCl salt when 6N HCl was added to an aq. soln. of fraction A. By chem. and phys. methods I was identified as β-[1-methyl-4[1-methyl-4-(1-methyl-4-formylaminopyrrole-2-carboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine. The structure of I was also confirmed by synthesis.
- 274Wada, M.; Doi, R.; Hosotani, R.; Higashide, S.; Ibuka, T.; Habashita, H.; Nakai, K.; Fujii, N.; Imamura, M. Effect of a new bombesin receptor antagonist, (E)-alkene bombesin isostere, on amylase release from rat pancreatic acini. Pancreas 1995, 10, 301– 305, DOI: 10.1097/00006676-199504000-00013[Crossref], [PubMed], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2MzltVWgtw%253D%253D&md5=17c58c008d4217538db88e560d997920Effect of a new bombesin receptor antagonist, (E)-alkene bombesin isostere, on amylase release from rat pancreatic aciniWada M; Doi R; Hosotani R; Higashide S; Ibuka T; Habashita H; Nakai K; Fujii N; Imamura MPancreas (1995), 10 (3), 301-5 ISSN:0885-3177.The short-chain pseudopeptide, [D-Phe6, Leu13 psi (CH2NH)Leu14]bombesin(6-14) (RDI), is reported to be a potent antagonist of bombesin, and development of this type of compound has greatly contributed to the investigation of biological actions of bombesin and its related peptides. We recently synthesized (E)-alkene bombesin isostere by replacing the peptide bond with an (E)-double bond: [D-Phe6, Leu13 psi [(E)CH = CH]Leu14] bombesin(6-14) (EABI). The present study examined the effect of EABI on amylase release from rat pancreatic acini. EABI showed no agonistic activity at concentrations up to 1 microM, and RBI showed slight agonistic activity at concentrations > 10 nM. EABI caused a dose-dependent inhibition of amylase release stimulated by 0.1 nM bombesin, with an IC50 of 6.7 +/- 1.7 nM, and induced almost-complete inhibition at 0.3 microM. RDI caused a dose-dependent inhibition of amylase release, with an IC50 of 68.7 +/- 16 nM. EABI caused a parallel and rightward shift of the entire dose-response curve of bombesin-stimulated amylase release, and the degree of the shift was dependent on the concentrations of EABI. EABI (100 nM) and RDI (100 nM) inhibited amylase releases stimulated by gastrin-releasing peptide (1 nM) and neuromedin-C (1 nM). In contrast, amylase release stimulated by cholecystokinin octapeptide (0.1 nM), carbachol (10 microM), vasoactive intestinal peptide (1 nM), and gastrin-17 (10 nM) was not inhibited by EABI and RDI. The results indicate that EABI is a potent and specific bombesin receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
- 275Mishra, C. B.; Gusain, S.; Shalini, S.; Kumari, S.; Prakash, A.; Kumari, N.; Yadav, A. K.; Kumari, J.; Kumar, K.; Tiwari, M. Development of novel carbazole derivatives with effective multifunctional action against Alzheimer’s diseases: design, synthesis, in silico, in vitro and in vivo investigation. Bioorg. Chem. 2020, 95, 103524, DOI: 10.1016/j.bioorg.2019.103524[Crossref], [PubMed], [CAS], Google Scholar275https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFeqtb8%253D&md5=89b85d7b09dfa362d87b00574b30289eDevelopment of novel carbazole derivatives with effective multifunctional action against Alzheimer's diseases: Design, synthesis, in silico, in vitro and in vivo investigationMishra, Chandra Bhushan; Gusain, Siddharth; Shalini, Shruti; Kumari, Shikha; Prakash, Amresh; Kumari, Namrata; Yadav, Anita Kumari; Kumari, Jyoti; Kumar, Kundan; Tiwari, ManishaBioorganic Chemistry (2020), 95 (), 103524CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)Carbazole based novel multifunctional agents has been rationally designed and synthesized as potential anti-Alzheimer agents. Multi-functional activity of these derivs. have been assessed by performing various in-vitro assays and these compds. appeared to be potent AChE inhibitors, Aβ aggregation inhibitors, anti-oxidant and neuroprotective agents. Among the entire series, MT-1 and MT-6 were most potent multifunctional agents which displayed effective and selective AChE inhibition, Aβ disaggregation, anti-oxidant and metal chelation action. Neuroprotective activity of MT-6 has been examd. against H2O2 induced toxicity in SHSY-5Y cells and they have shown effective neuroprotection. Addnl., MT-6 did not display any significant toxicity in SHSY-5Y cells, indicating its non-toxic nature. Mol. docking and MD simulation studies have been also performed to explore mol. level interaction with AChE and Aβ. Finally, MT-6 was evaluated against scopolamine induced dementia model of mice and this compd. actively improved memory deficit and cognition impairment in scopolamine treated mice. Thus, novel carbazole deriv. MT-6 has been explored as an effective and safe multifunctional agent against AD and this mol. may be used as a suitable lead for development of effective anti-Alzheimer agents in future.
- 276Mishra, C. B.; Kumari, S.; Manral, A.; Prakash, A.; Saini, V.; Lynn, A. M.; Tiwari, M. Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer’s disease. Eur. J. Med. Chem. 2017, 125, 736– 750, DOI: 10.1016/j.ejmech.2016.09.057[Crossref], [PubMed], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1Clsb7J&md5=a0fb77041f4b505ed678700ac9a5a97aDesign, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer's diseaseMishra, Chandra Bhushan; Kumari, Shikha; Manral, Apra; Prakash, Amresh; Saini, Vikas; Lynn, Andrew M.; Tiwari, ManishaEuropean Journal of Medicinal Chemistry (2017), 125 (), 736-750CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A novel series of donepezil based multi-functional agents (E)-dimethoxy-((substituted piperazinyl)benzylidene)-dihydro-indenones I [R = Ph, 2-pyridyl, C(O)-(2-furyl), etc.] was designed and synthesized as potential anti-Alzheimer's agents. In-vitro studies revealed that these compds. demonstrated moderate to good AChE and Aβ aggregation inhibitory activity. These derivs. were also endowed with admirable antioxidant activity. Among the entire series compds. I [R = CH(4-FC6H4)2, 2-pyridyl, C(O)-(2-furyl)] appeared as most active multi-functional agents and displayed marked AChE inhibitory, Aβ disaggregation and antioxidant activity. Studies indicated that I [R = 2-pyridyl, C(O)-(2-furyl)] showed better AChE inhibitory activity than the std. drug donepezil and I [R = CH(4-FC6H4)2, 2-pyridyl, C(O)-(2-furyl)] exhibited better Aβ aggregation inhibitory activity than curcumin. These compds. successfully diminished H2O2 induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2 as well as Aβ induced toxicity in SH-SY5Y cells in a concn. dependent manner. Moreover, these derivs. did not exerted any significant toxicity in neuronal SH-SY5Y cells in cytotoxicity assay. To elucidate the plausible binding mode of these compds., mol. docking studies and mol. dynamics (MD) simulation studies were also performed and the results indicated their significant interactions with the active sites of AChE as well as Aβ1-42 peptide. Thus, the present study evidently showed that, the most active compds. were potent multi-functional agents against Alzheimer's disease and might serve as promising lead candidates for anti-Alzheimer drug development.
- 277Mishra, C. B.; Manral, A.; Kumari, S.; Saini, V.; Tiwari, M. Design, synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition, anti-β-amyloid aggregation, antioxidant and neuroprotection properties against Alzheimer’s disease. Bioorg. Med. Chem. 2016, 24, 3829– 3841, DOI: 10.1016/j.bmc.2016.06.027[Crossref], [PubMed], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVKnt7bN&md5=a77f2e5c5a6d642a703bf41c1735d421Design, synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition, anti-β-amyloid aggregation, antioxidant and neuroprotection properties against Alzheimer's diseaseMishra, Chandra Bhushan; Manral, Apra; Kumari, Shikha; Saini, Vikas; Tiwari, ManishaBioorganic & Medicinal Chemistry (2016), 24 (16), 3829-3841CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)-1H-indene-1,3(2H)-diones were designed, synthesized and appraised as multifunctional anti-Alzheimer agents. In vitro studies of compds. 27-38 showed that these compds. exhibit moderate to excellent AChE, BuChE and Aβ aggregation inhibitory activity. Notably, compds. 34 and 38 appeared as most active multifunctional agents in the entire series and exhibited excellent inhibition against AChE (IC50 = 0.048 μM: 34; 0.036 μM: 38), Aβ aggregation (max% inhibition 82.2%, IC50 = 9.2 μM: 34; max% inhibition 80.9%, IC50 = 10.11 μM: 38) and displayed significant antioxidant potential in ORAC-FL assay. Both compds. also successfully diminished H2O2 induced oxidative stress in SH-SY5Y cells. Fascinatingly, compds. 34 and 38 showed admirable neuroprotective effects against H2O2 and Aβ induced toxicity in SH-SY5Y cells. Addnl., both derivs. showed no considerable toxicity in neuronal cell viability assay and represented drug likeness properties in the primarily pharmacokinetics study. All these results together, propelled out that compds. 34 and 38 might serve as promising multi-functional lead candidates for treatment of AD in the future.
- 278Fu, Y.; Bieschke, J.; Kelly, J. W. E-olefin dipeptide isostere incorporation into a polypeptide backbone enables hydrogen bond perturbation: probing the requirements for Alzheimer’s amyloidogenesis. J. Am. Chem. Soc. 2005, 127, 15366– 15367, DOI: 10.1021/ja0551382[ACS Full Text], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFahsbbK&md5=3c322f177ef34107a06835b91c936ef3E-Olefin Dipeptide Isostere Incorporation into a Polypeptide Backbone Enables Hydrogen Bond Perturbation: Probing the Requirements for Alzheimer's AmyloidogenesisFu, Yanwen; Bieschke, Jan; Kelly, Jeffery W.Journal of the American Chemical Society (2005), 127 (44), 15366-15367CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The authors report the stereospecific synthesis of an E-olefin dipeptide (2R,3E,5S)-isostere, BocNHCH(CH2Ph)CH:CHCH(CH2Ph)CO2H, that can be used to make gram quantities of the Phe-Phe isostere desired for eliminating a specific backbone H-bond donor and acceptor in the Alzheimer's disease related Aβ peptide. The Aβ(1-40) peptide contg. the E-olefin isostere in place of Phe19-Phe20 was prepd. by solid-phase peptide synthesis and was subjected to amyloidogenesis conditions. This Aβ(1-40) peptide analog can aggregate into spherical morphologies but does not progress on to form protofibrils or fibrils as is the case for the all-amide sequence, providing insight into the structural requirements for amyloidogenesis.
- 279Shue, Y. K.; Tufano, M. D.; Carrera, G. M., Jr.; Kopecka, H.; Kuyper, S. L.; Holladay, M. W.; Lin, C. W.; Witte, D. G.; Miller, T. R.; Stashko, M.; Nadzan, A. M. Double bond isosteres of the peptide bond: synthesis and biological activity of cholecystokinin (CCK) C-terminal hexapeptide analogs. Bioorg. Med. Chem. 1993, 1, 161– 171, DOI: 10.1016/S0968-0896(00)82117-3[Crossref], [PubMed], [CAS], Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXhsFeqs78%253D&md5=2490ba46a4540221edce7cfe7a9be7f7Double bond isosteres of the peptide bond: synthesis and biological activity of cholecystokinin (CCK) C-terminal hexapeptide analogsShue, Youe Kong; Tufano, Michael D.; Carrera, George M., Jr.; Kopecka, Hana; Kuyper, Sharon L.; Holladay, Mark W.; Lin, Chun Wel; Witte, David G.; Miller, Thomas R.; et al.Bioorganic & Medicinal Chemistry (1993), 1 (3), 161-71CODEN: BMECEP; ISSN:0968-0896.New and existing methodologies were used to prep. a series of modified CCK analogs in which each amide bond was replaced by a trans-alkene unit. The data indicate that every amide linkage at C-terminal tetrapeptide (CCK-4) region is crucial for biol. activity. The amide bond beyond the Trp residue in the N-terminus can be replaced by a trans-alkene without affecting most of the binding potency and functional activity.
- 280Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 2018, 61, 5822– 5880, DOI: 10.1021/acs.jmedchem.7b01788[ACS Full Text], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2qu7w%253D&md5=2d0ce3326c7ff932da8d7d26972ced14Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug DesignMeanwell, Nicholas A.Journal of Medicinal Chemistry (2018), 61 (14), 5822-5880CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the Me group while also acting as a functional mimetic of the carbonyl, carbinol, andnitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metab., membrane permeability, and P-gp recognition of a mol. and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated mol. construction that broadens biol. mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a mol. are summarized.
- 281Pasternak, G. W.; Pan, Y. X. Mu opioids and their receptors: evolution of a concept. Pharmacol. Rev. 2013, 65, 1257– 1317, DOI: 10.1124/pr.112.007138[Crossref], [PubMed], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvV2rtLzJ&md5=49f6dc7f031f9302b72710d42f2a00eaMu opioids and their receptors: evolution of a conceptPasternak, Gavril W.; Pan, Ying-XianPharmacological Reviews (2013), 65 (4), 1257-1317CODEN: PAREAQ; ISSN:1521-0081. (American Society for Pharmacology and Experimental Therapeutics)A review. Opiates arc among the oldest medications available to manage a no. of medical problems. Although pain is the current focus, early use initially focused upon the treatment of dysentery. Opium contains high concns. of both morphine and codeine, along with thebaine, which is used in the synthesis of a no. of semisynthetic opioid analgesics. Thus, it is not surprising that new agents were initially based upon the morphine scaffold. The concept of multiple opioid receptors was first suggested almost 50 years ago, opening the possibility of new classes of drugs, but the morphine-like agents have remained the mainstay in the medical management of pain. Termed mu, our understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years. Early pharmacol. studies identified three major classes of receptors, helped by the discovery of endogenous opioid peptides and receptor subtypes-primarily through the synthesis of novel agents. These chem. biol. approaches were then eclipsed by the mol. biol. revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated.
- 282Weinberger, S. B.; Martinez, J. L., Jr. Characterization of hydrolysis of [leu]enkephalin and D-ala2-[L-leu]enkephalin in rat plasma. J. Pharmacol. Exp. Ther. 1988, 247, 129– 135[PubMed], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXmt1artLg%253D&md5=a79b38ac0b0767259539514956d97377Characterization of hydrolysis of [Leu]enkephalin and D-Ala2-[L-Leu]enkephalin in rat plasmaWeinberger, Susan B.; Martinez, Joe L., Jr.Journal of Pharmacology and Experimental Therapeutics (1988), 247 (1), 129-35CODEN: JPETAB; ISSN:0022-3565.Based on differences in total metabolite accumulation in the presence or absence of selective peptidase inhibitors, rat plasma is found to have its own unique pattern of enkephalin hydrolysis. Approx. 85-90% of the hydrolysis of [Leu5]enkephalin is attributed to the combined action of aminopeptidase M and angiotensin-converting enzyme, whereas enkephalinase and aminopeptidase MII activity against [Leu5]enkephalin are not detectable. Similarly, 80-90% of the hydrolysis of D-Ala2-[L-Leu5]enkephalin (DALLE) is due to the combined action of aminopeptidase M and angiotensin-converting enzyme, whereas aminopeptidase MII and enkephalinase activity against this substrate also could not be detected. This is in contrast to the high susceptibility to hydrolysis by enkephalinase, and the low susceptibility to aminopeptidase activity, for DALLE in brain tissue. Among other alternatives, it is suggested that enkephalin hydrolysis in plasma may appear to be unique because of differences in enzyme conformation and(or) the availability of a substance(s) that competes with, or alters the binding of, [Leu5]enkephalin, DALLE, or the inhibitors to the enzymes.
- 283Thompson, S. E.; Audus, K. L. Leucine-enkephalin metabolism in brain microvessel endothelial cells. Peptides 1994, 15, 109– 116, DOI: 10.1016/0196-9781(94)90178-3[Crossref], [PubMed], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXhvVens7c%253D&md5=aa361d0a0cd198493a8f83a09c4275afLeucine-enkephalin metabolism in brain microvessel endothelial cellsThompson, Suzanne E.; Audus, Kenneth L.Peptides (New York, NY, United States) (1994), 15 (1), 109-16CODEN: PPTDD5; ISSN:0196-9781.The metab. of leucine-enkephalin (LE) was investigated in primary cultures of bovine brain microvessel endothelial cell (BMEC) monolayers. LE was hydrolyzed slowly with < 40% of the peptide metabolized following a 5-h incubation with intact BMEC monolayers at 37°. Following sepn. and extn. of BMEC enzymes into cytosolic and membrane-bound fractions, LE was obsd. to be labile in the presence of both cytosolic and membrane-assocd. enzymes. A much greater concn. of enkephalin-hydrolyzing enzyme was assocd. with the cytosolic fraction. Resulting metabolite profiles for LE appeared to be the result of interactions of the peptide with primarily aminopeptidases and angiotensin-converting enzyme. Apparently, extensive metab. of LE solely by BMECs in the cerebrovasculature would require internalization by the cells and presentation to cytosolic enzymes.
- 284Karad, S. N.; Pal, M.; Crowley, R. S.; Prisinzano, T. E.; Altman, R. A. Synthesis and opioid activity of Tyr1-ψ[(Z)CF=CH]-Gly2 and Tyr1-ψ[(S)/(R)-CF3CH-NH]-Gly2 leu-enkephalin fluorinated peptidomimetics. ChemMedChem 2017, 12, 571– 576, DOI: 10.1002/cmdc.201700103[Crossref], [PubMed], [CAS], Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlsFOhtrk%253D&md5=dd84cc96cffca016898836a47604d917Synthesis and opioid activity of Tyr1-ψ[(Z)CF=CH]-Gly2 and Tyr1-ψ[(S)/(R)-CF3CH-NH]-Gly2 Leu-enkephalin fluorinated peptidomimeticsKarad, Somnath Narayan; Pal, Mohan; Crowley, Rachel S.; Prisinzano, Thomas E.; Altman, Ryan A.ChemMedChem (2017), 12 (8), 571-576CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr1-ψ[(Z)CF=CH]-Gly2) and trifluoroethylamine (Tyr1-ψ[(S)/(R)-CF3CH-NH]-Gly2) analogs of the endogenous opioid neuropeptide, Leu-enkephalin. The fluoroalkene peptidomimetic exhibited low nanomolar functional activity (5.0±2 nM and 60±15 nM for δ- and μ-opioid receptors, resp.) with a μ/δ-selectivity ratio that mimics that of the natural peptide. However, the trifluoroethylamine peptidomimetics, irresp. of stereochem., did not activate the opioid receptors, which suggest that bulky CF3 substituents are not tolerated at this position.
- 285Altman, R. A.; Sharma, K. K.; Rajewski, L. G.; Toren, P. C.; Baltezor, M. J.; Pal, M.; Karad, S. N. Tyr1- ψ[( Z)CF=CH]-Gly2 fluorinated peptidomimetic improves distribution and metabolism properties of leu-enkephalin. ACS Chem. Neurosci. 2018, 9, 1735– 1742, DOI: 10.1021/acschemneuro.8b00085[ACS Full Text], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnsVGgt7Y%253D&md5=e2b298070c410d9e7455c2a6bc236c6fTyr1-ψ[(Z)CF=CH]-Gly2 fluorinated peptidomimetics improves distribution and metabolism properties of Leu-enkephalinAltman, Ryan A.; Sharma, Krishna K.; Rajewski, Lian G.; Toren, Paul C.; Baltezor, Michael J.; Pal, Mohan; Karad, Somnath N.ACS Chemical Neuroscience (2018), 9 (7), 1735-1742CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Opioid peptides are key regulators in cellular and intercellular physiol. responses, and could be therapeutically useful for modulating several pathol. conditions. Unfortunately, the use of peptide-based agonists to target centrally located opioid receptors is limited by poor physicochem. (PC), distribution, metabolic, and pharmacokinetic (DMPK) properties that restrict penetration across the blood-brain barrier via passive diffusion. To address these problems, the present paper exploits fluorinated peptidomimetics to simultaneously modify PC and DMPK properties, thus facilitating entry into the central nervous system. As an initial example, the present paper exploited the Tyr1-ψ[(Z)CF=CH]-Gly2 peptidomimetic to improve PC druglike characteristics (computational), plasma and microsomal degrdn., and systemic and CNS distribution of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). Thus, the fluoroalkene replacement transformed an instable in vitro tool compd. into a stable and centrally distributed in vivo probe. In contrast, the Tyr1-ψ[CF3CH2-NH]-Gly2 peptidomimetic decreased stability by accelerating proteolysis at the Gly3-Phe4 position.
- 286Nadon, J. F.; Rochon, K.; Grastilleur, S.; Langlois, G.; Dao, T. T.; Blais, V.; Guerin, B.; Gendron, L.; Dory, Y. L. Synthesis of Gly-ψ[(Z)CF=CH]-Phe, a fluoroalkene dipeptide isostere, and its incorporation into a leu-enkephalin peptidomimetic. ACS Chem. Neurosci. 2017, 8, 40– 49, DOI: 10.1021/acschemneuro.6b00163[ACS Full Text], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslSisLnI&md5=893e2b2d560b04eebac0139a6830c42bSynthesis of Gly-ψ[(Z)CF=CH]-Phe, a fluoroalkene dipeptide isostere, and its incorporation into a Leu-enkephalin peptidomimeticNadon, Jean-Francois; Rochon, Kristina; Grastilleur, Sebastien; Langlois, Guillaume; Dao, Thi Thanh Ha; Blais, Veronique; Guerin, Brigitte; Gendron, Louis; Dory, Yves L.ACS Chemical Neuroscience (2017), 8 (1), 40-49CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)A new Leu-enkephalin peptidomimetic designed to explore the hydrogen bond acceptor ability of the third peptide bond has been prepd. and studied. This new analog is produced by replacing the third amide of Leu-enkephalin with a fluoroalkene. An efficient and innovative synthesis of the corresponding dipeptide surrogate Fmoc-Gly-ψ[(Z)CF=CH]-Phe-OH is described. The key step involves the alkylation of a tin dienolate from the less hindered face of its chiral sulfonamide auxiliary derived from camphor. Once its synthesis was complete, its incorporation into the peptidomimetic sequence was achieved on a solid support with chlorotrityl resin following the Fmoc (Fmoc = 9-fluorenylmethoxycarbonyl) strategy. The peptidomimetic was characterized using competition binding with [125I]-deltorphin I on membrane exts. of HEK293 cells expressing the mouse delta opioid receptor (DOPr) and based on its abilities to inhibit the elec. induced contractions of the mouse vas deferens and to activate the ERK1/2 signaling pathway in DRGF11/DOPr-GFP cells. Together with our previous observations, our findings strongly suggest that the third amide bond of Leu-enkephalin primarily acts as a hydrogen bond acceptor in DOPr. Consequently, this amide bond can be successfully replaced by an ester, a thioamide, or a fluoroalkene without greatly impacting the binding or biol. activity of the corresponding analogs. The lipophilicity (LogD7.4) of the active analog was also measured. It appears that fluoroalkenes are almost as efficient at increasing the lipophilicity as normal alkenes.
- 287Lajoie, G.; Lepine, F.; Lemaire, S.; Jolicoeur, F.; Aube, C.; Turcotte, A.; Belleau, B. Synthesis and biological activity of monothionated analogs of leucine-enkephalin. Int. J. Pept. Protein Res. 1984, 24, 316– 327, DOI: 10.1111/j.1399-3011.1984.tb00959.x[Crossref], [PubMed], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXps1Smsg%253D%253D&md5=995c8b138036a4879c0176ebeb283fb3Synthesis and biological activity of monothionated analogs of leucine-enkephalinLajoie, Gilles; Lepine, Francois; Lemaire, Simon; Jolicoeur, Francois; Aube, Carl; Turcotte, Andree; Belleau, BernardInternational Journal of Peptide & Protein Research (1984), 24 (4), 316-27CODEN: IJPPC3; ISSN:0367-8377.Title analogs H-DL-Tyr(S)-Gly-Gly-Phe-Leu-OH (I), H-Tyr-Gly(S)-Gly-Phe-Leu-OH (II), H-Tyr-Gly-Gly(S)-Phe-Leu-OH (III), and H-Tyr-Gly-Gly-Phe(S)-Leu-OH (IV) were prepd. and their opiate-like and analgesic activities were detd. Thus, Boc-Tyr(Boc)-NHMe (Boc = Me3CO2C) was thionated by 2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiophosphetane 2,4-disulfite to give Boc-Tyr(Boc)(S)-NHMe, which was S-methylated with MeI to give p-(BocO)C6H4CH2CH(NHBoc)C(SMe):NMe.HI, which was treated with H2S to give Boc-Tyr(Boc)(S)-SMe (V). Boc-Gly-Gly-Phe-Leu-OMe was Boc-deblocked and then coupled with V to give Boc-DL-Tyr(Boc)(S)-Gly-Gly-Phe-Leu-OMe, which was Boc-deblocked to give I. The biol. activities of I-IV depend on the backbone position of the thioamide function. The results are interpreted in terms of the thioamide function in receptor recognition processes, the probable behavior of thiopeptides toward physiol. relevant peptidases, and the structural divergences between tissue-sp. receptors.
- 288Proteau-Gagne, A.; Bournival, V.; Rochon, K.; Dory, Y. L.; Gendron, L. Exploring the backbone of enkephalins to adjust their pharmacological profile for the δ-opioid receptor. ACS Chem. Neurosci. 2010, 1, 757– 769, DOI: 10.1021/cn1000759[ACS Full Text], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFOis7jL&md5=b7e950764170a6b0482a75122b2b705fExploring the Backbone of Enkephalins To Adjust Their Pharmacological Profile for the δ-Opioid ReceptorProteau-Gagne, Arnaud; Bournival, Veronique; Rochon, Kristina; Dory, Yves L.; Gendron, LouisACS Chemical Neuroscience (2010), 1 (11), 757-769CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)The role of each of the four amide bonds in Leu5-enkephalin was investigated by systematically and sequentially replacing each with its corresponding trans-alkene. Six Leu5-enkephalin analogs based on six dipeptide surrogates and two Met5-enkephalin analogs were synthesized and thoroughly tested using a δ-opioid receptor internalization assay, an ERK1/2 activation assay, and a competition binding assay to evaluate their biol. properties. We obsd. that an E-alkene can efficiently replace the first amide bond of Leu5- and Met5-enkephalin without significantly affecting biol. activity. By contrast, the second amide bond was found to be highly sensitive to the same modification, suggesting that it is involved in biol. essential intra- or intermol. interactions. Finally, we obsd. that the affinity and activity of analogs contg. an E-alkene at either the third or fourth position were partially reduced, indicating that these amide bonds are less important for these intra- or intermol. interactions. Overall, our study demonstrates that the systematic and sequential replacement of amide bonds by E-alkene represents an efficient way to explore peptide backbones.
- 289Lee, C.; Ma, H.; Hang, J. Q.; Leveque, V.; Sklan, E. H.; Elazar, M.; Klumpp, K.; Glenn, J. S. The hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral protein. Virology 2011, 414, 10– 18, DOI: 10.1016/j.virol.2011.03.026[Crossref], [PubMed], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlvVyit7c%253D&md5=b4212a1dd1365aedfd384e685afdefebThe hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral proteinLee, Choongho; Ma, Han; Hang, Julie Qi; Leveque, Vincent; Sklan, Ella H.; Elazar, Menashe; Klumpp, Klaus; Glenn, Jeffrey S.Virology (2011), 414 (1), 10-18CODEN: VIRLAX; ISSN:0042-6822. (Elsevier B.V.)The hepatitis C virus (HCV) non-structural (NS) 5A protein plays an essential role in the replication of the viral RNA by the membrane-assocd. replication complex (RC). Recently, a putative NS5A inhibitor, BMS-790052, exhibited the highest potency of any known anti-HCV compd. in inhibiting HCV replication in vitro and showed a promising clin. effect in HCV-infected patients. The precise mechanism of action for this new class of potential anti-HCV therapeutics, however, is still unclear. In order to gain further insight into its mode of action, we sought to test the hypothesis that the antiviral effect of BMS-790052 might be mediated by interfering with the functional assembly of the HCV RC. We obsd. that BMS-790052 indeed altered the subcellular localization and biochem. fractionation of NS5A. Taken together, our data suggest that NS5A inhibitors such as BMS-790052 can suppress viral genome replication by altering the proper localization of NS5A into functional RCs.
- 290Chang, W.; Mosley, R. T.; Bansal, S.; Keilman, M.; Lam, A. M.; Furman, P. A.; Otto, M. J.; Sofia, M. J. Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics. Bioorg. Med. Chem. Lett. 2012, 22, 2938– 2942, DOI: 10.1016/j.bmcl.2012.02.051[Crossref], [PubMed], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XktV2qtLk%253D&md5=513fc896ce045cbf1a236d75bb75b29cInhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimeticsChang, Wonsuk; Mosley, Ralph T.; Bansal, Shalini; Keilman, Meg; Lam, Angela M.; Furman, Phillip A.; Otto, Michael J.; Sofia, Michael J.Bioorganic & Medicinal Chemistry Letters (2012), 22 (8), 2938-2942CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-mol. hydrogen bonds were a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin contg. inhibitor exhibited picomolar activity (EC50 = 79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A.
- 291Evelyn, C. R.; Bell, J. L.; Ryu, J. G.; Wade, S. M.; Kocab, A.; Harzdorf, N. L.; Showalter, H. D. H.; Neubig, R. R.; Larsen, S. D. Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423. Bioorg. Med. Chem. Lett. 2010, 20, 665– 672, DOI: 10.1016/j.bmcl.2009.11.056[Crossref], [PubMed], [CAS], Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsF2iur%252FO&md5=e931712238b9376b45c6e40daac3fda8Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423Evelyn, Chris R.; Bell, Jessica L.; Ryu, Jenny G.; Wade, Susan M.; Kocab, Andrew; Harzdorf, Nicole L.; Showalter, H. D. Hollis; Neubig, Richard R.; Larsen, Scott D.Bioorganic & Medicinal Chemistry Letters (2010), 20 (2), 665-672CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)We recently identified bis(amide) CCG-1423 (1) as a novel inhibitor of RhoA/C-mediated gene transcription that is capable of inhibiting invasion of PC-3 prostate cancer cells in a Matrigel model of metastasis. An initial structure-activity relationship study focusing on bioisosteric replacement of the amides and conformational restriction identified two compds., 4g and 8, with improved selectivity for inhibition of RhoA/C-mediated gene transcription and attenuated cytotoxicity relative to 1. Both compds. were also capable of inhibiting cell invasion with equal efficacy to 1 but with less attendant cytotoxicity.
- 292Canales, E.; Carlson, J. S.; Appleby, T.; Fenaux, M.; Lee, J.; Tian, Y.; Tirunagari, N.; Wong, M.; Watkins, W. J. Tri-substituted acylhydrazines as tertiary amide bioisosteres: HCV NS5B polymerase inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 4288– 4292, DOI: 10.1016/j.bmcl.2012.05.025[Crossref], [PubMed], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotVejtrY%253D&md5=5b3556448780b77b93743f2bf707c995Tri-substituted acylhydrazines as tertiary amide bioisosteres: HCV NS5B polymerase inhibitorsCanales, Eda; Carlson, Joseph S.; Appleby, Todd; Fenaux, Martijn; Lee, Johnny; Tian, Yang; Tirunagari, Neeraj; Wong, Melanie; Watkins, William J.Bioorganic & Medicinal Chemistry Letters (2012), 22 (13), 4288-4292CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The use of a tri-substituted acylhydrazine as an isostere of a tertiary amide was explored in a series of HCV NS5B thumb site II inhibitors. Direct replacement generated an analog with similar conformational and physicochem. properties. The series was extended to produce compds. with potent binding affinities and encouraging levels of cellular potency.
- 293Trippier, P. C. Selecting good ‘drug-like’ properties to optimize small molecule blood-brain barrier penetration. Curr. Med. Chem. 2016, 23, 1392– 1407, DOI: 10.2174/0929867323666160405112353[Crossref], [PubMed], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XptVWlurw%253D&md5=8edfbeec9c34759a5ecc809b645794d5Selecting Good 'Drug-Like' Properties to Optimize Small Molecule Blood-Brain Barrier PenetrationTrippier, Paul C.Current Medicinal Chemistry (2016), 23 (14), 1392-1407CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)The success rate to achieve clin. approval of drugs developed to treat diseases of the central nervous system (CNS) is the lowest of all disease indications. A large contributor to this poor success rate is failure of small mols. to pass through the blood-brain barrier (BBB), a barrier composed of capillary endothelial cells connected by tight junctions that functions to extrude xenobiotics from the brain. Designing small mols. to be BBB penetrant has been the subject of intensive research and has resulted in a series of guidelines to attain the best possible chances of BBB penetration. This review will analyze the current state of thinking in ranking the importance of various physicochem. properties required to select BBB penetrant mols., describe model systems to det. BBB penetration, summarize data anal. methods and provide an outlook on further developments in the field.
- 294Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fischer, H.; Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Oxetanes as promising modules in drug discovery. Angew. Chem., Int. Ed. 2006, 45, 7736– 7739, DOI: 10.1002/anie.200602343[Crossref], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht12rsrfK&md5=cd500bc1cff28f16b9dc3a2f1b9895bfOxetanes as promising modules in drug discoveryWuitschik, Georg; Rogers-Evans, Mark; Mueller, Klaus; Fischer, Holger; Wagner, Bjoern; Schuler, Frnaz; Polonnchuk, Liudmila; Carreira, Erick M.Angewandte Chemie, International Edition (2006), 45 (46), 7736-7739CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Introduction of an oxetane ring results in remarkably improved physico- and biochem. properties of the underlying scaffold. The oxetane ring confers enhanced soly., reduces the metabolic degrdn., lipophilicity, and amphiphilicity, and modulates the basicity of a nearby amine group.
- 295Bull, J. A.; Croft, R. A.; Davis, O. A.; Doran, R.; Morgan, K. F. Oxetanes: recent advances in synthesis, reactivity, and medicinal chemistry. Chem. Rev. 2016, 116, 12150– 12233, DOI: 10.1021/acs.chemrev.6b00274[ACS Full Text], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFWqtrfN&md5=a65f330a32a3e131ec5b60280382bfe4Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal ChemistryBull, James A.; Croft, Rosemary A.; Davis, Owen A.; Doran, Robert; Morgan, Kate F.Chemical Reviews (Washington, DC, United States) (2016), 116 (19), 12150-12233CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. The four-membered oxetane ring has been increasingly exploited for its contrasting behaviors: its influence on physicochem. properties as a stable motif in medicinal chem. and its propensity to undergo ring-opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivs. This review takes an overview of the literature for the synthesis of oxetane derivs., concg. on advances in the last five years up to the end of 2015. These methods are clustered by strategies for prepn. of the ring and further derivatization of preformed oxetane-contg. building blocks. Examples of the use of oxetanes in medicinal chem. are reported, including a collation of oxetane derivs. appearing in recent patents for medicinal chem. applications. Finally, examples of oxetane derivs. in ring-opening and ring-expansion reactions are described.
- 296McLaughlin, M.; Yazaki, R.; Fessard, T. C.; Carreira, E. M. Oxetanyl peptides: novel peptidomimetic modules for medicinal chemistry. Org. Lett. 2014, 16, 4070– 4073, DOI: 10.1021/ol501590n[ACS Full Text], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1ansr7K&md5=120bb06c0cdd08cd83be7f2e56ad0f8cOxetanyl Peptides: Novel Peptidomimetic Modules for Medicinal ChemistryMcLaughlin, Martin; Yazaki, Ryo; Fessard, Thomas C.; Carreira, Erick M.Organic Letters (2014), 16 (16), 4070-4073CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)The synthesis of novel oxetanyl peptides, where the amide bond is replaced by a non-hydrolyzable oxetanylamine fragment, is reported. This new class of pseudo-dipeptides with the same H-bond donor/acceptor pattern found in proteins expands the repertoire of peptidomimetics.
- 297Powell, N. H.; Clarkson, G. J.; Notman, R.; Raubo, P.; Martin, N. G.; Shipman, M. Synthesis and structure of oxetane containing tripeptide motifs. Chem. Commun. 2014, 50, 8797– 8800, DOI: 10.1039/C4CC03507K[Crossref], [PubMed], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVGnsLrK&md5=1838a361bfebb38658c8f3a2c2855934Synthesis and structure of oxetane containing tripeptide motifsPowell, Nicola H.; Clarkson, Guy J.; Notman, Rebecca; Raubo, Piotr; Martin, Nathaniel G.; Shipman, MichaelChemical Communications (Cambridge, United Kingdom) (2014), 50 (63), 8797-8800CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A new class of peptidomimetic is reported in which one of the amide C:O bonds of the peptide backbone is replaced by an oxetane ring. They are synthesized by conjugate addn. of various α-amino esters to a 3-(nitromethylene)oxetane, redn. of the nitro group and further coupling with N-Z protected amino acids to grow the peptide chain. Structural insights are provided by X-ray diffraction and mol. dynamics simulations.
- 298Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Muller, K. Oxetanes in drug discovery: structural and synthetic insights. J. Med. Chem. 2010, 53, 3227– 3246, DOI: 10.1021/jm9018788[ACS Full Text], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjvFKjt7s%253D&md5=e95742d38e933c2fb0d76d638ccc773cOxetanes in Drug Discovery: Structural and Synthetic InsightsWuitschik, Georg; Carreira, Erick M.; Wagner, Bjorn; Fischer, Holger; Parrilla, Isabelle; Schuler, Franz; Rogers-Evans, Mark; Muller, KlausJournal of Medicinal Chemistry (2010), 53 (8), 3227-3246CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The use of oxetanes as replacements for gem-di-Me or carbonyl groups and their effects on the aq. soly., lipophilicity, metabolic stability, and conformation for various compds. are studied; methods for the prepn. of a variety of substituted oxetanes are given. The magnitude of changes in properties and in metabolic stability with oxetane substitution depends on the structural context; for example, substitution of a gem-di-Me group with an oxetane, aq. soly. may increase by a factor of 4 to more than 4000 while reducing the rate of metabolic degrdn. in most cases. Incorporation of an oxetane into an aliph. chain increases in some cases the preference for synclinal conformations rather than antiplanar conformations of the chain. Spirocyclic oxetanes such as an oxazaspiroheptane resemble commonly used fragments in drug discovery, such as morpholines, and in some cases increase aq. soly. more effectively than morpholines. An improved chemoselective oxidn. of 3-oxetanol to 3-oxetanone is disclosed; olefination of 3-oxetanone by a variety of methods yields alkylideneoxetanes I [R = (EtO)2P(:O), OHC, O2N, EtO2C, NC, PhO2S, MeCO, 1-(4-chlorophenyl)-1-cyclobutanecarbonyl]. I (R = EtO2C, OHC, O2N) undergo addn. reactions with nucleophiles such as amines, carbonyl compds., and arylboronic acids to give oxetanes such as II. The crystal structures of a variety of oxetanes are detd.
- 299Beadle, J. D.; Powell, N. H.; Raubo, P.; Clarkson, G. J.; Shipman, M. Synthesis of oxetane- and azetidine-containing spirocycles related to the 2,5-diketopiperazine framework. Synlett 2015, 27, 169– 172, DOI: 10.1055/s-0035-1560593
- 300Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 2009, 52, 6752– 6756, DOI: 10.1021/jm901241e[ACS Full Text], [CAS], Google Scholar300https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1KjtLvN&md5=4ca92c30c17c53d77ad376719bad951eEscape from Flatland: Increasing Saturation as an Approach to Improving Clinical SuccessLovering, Frank; Bikker, Jack; Humblet, ChristineJournal of Medicinal Chemistry (2009), 52 (21), 6752-6756CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The medicinal chem. community has become increasingly aware of the value of tracking calcd. phys. properties such as mol. wt., topol. polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. The authors hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose mols. to fail by steering discovery efforts toward achiral, arom. compds. The authors have proposed two simple and interpretable measures of the complexity of mols. prepd. as potential drug candidates. The first is carbon bond satn. as defined by fraction Sp3 (Fsp3) where Fsp3 = (no. of Sp3 hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the mol. The authors demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compds. transition from discovery, through clin. testing, to drugs. To explain these observations, the authors further demonstrate that satn. correlates with soly., an exptl. phys. property important to success in the drug discovery setting.
- 301Trippier, P. C.; McGuigan, C. Boronic acids in medicinal chemistry: anticancer, antibacterial and antiviral applications. MedChemComm 2010, 1, 183– 198, DOI: 10.1039/c0md00119h[Crossref], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVymt7vO&md5=27d8b40712213a0eaab370f3010033cfBoronic acids in medicinal chemistry: anticancer, antibacterial and antiviral applicationsTrippier, Paul C.; McGuigan, ChristopherMedChemComm (2010), 1 (3), 183-198CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A review. In 2003, bortezomib, a first-in-class therapeutic, gained approval from the US Federal Drug Administration for the treatment of relapsed multiple myeloma and mantle cell lymphoma. Approval in the UK, for multiple myeloma, followed in 2006. Bortezomib contains a boronic acid, a functional group that has become increasingly more commonplace within the medicinal chem. literature. The introduction of this drug has sparked a renewed interest in the investigation of boronic acids as drugs for a wide range of diseases. This review will guide the reader through the most recent developments in this field, by considering in turn, the biol. target's amenable to the action of boronic acids.
- 302Fernandes, G. F. S.; Denny, W. A.; Dos Santos, J. L. Boron in drug design: recent advances in the development of new therapeutic agents. Eur. J. Med. Chem. 2019, 179, 791– 804, DOI: 10.1016/j.ejmech.2019.06.092[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtleju7fE&md5=52c7677a4b6213be8a03b48c3981bba4Boron in drug design: Recent advances in the development of new therapeutic agentsFernandes, Guilherme Felipe Santos; Denny, William Alexander; Dos Santos, Jean LeandroEuropean Journal of Medicinal Chemistry (2019), 179 (), 791-804CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Advances in the field of boron chem. have expanded the application of this element in Medicinal Chem. Boron-contg. compds. represent a new class for medicinal chemists to use in their drug designs. Bortezomib, a dipeptide boronic acid approved by the FDA in 2003 for treatment of multiple myeloma, paved the way for the discovery of new boron-contg. compds. After its approval, two other boron-contg. compds. have been approved, tavaborole for the treatment of onychomycosis and crisaborole for the treatment of mild to moderate atopic dermatitis. A no. of boron-contg. compds. have been described and evaluated for a plethora of therapeutic applications. The present review is intended to highlight the recent advances related to boron-contg. compds. and their therapeutic applications. Here, we focused only in those most biol. active compds. with proven in vitro and/or in vivo efficacy in the therapeutic area published in the last years.
- 303Malde, A. K.; Khedkar, S. A.; Coutinho, E. C. The B(OH)–NH analog is a surrogate for the amide bond (CO–NH) in peptides: an ab initio Study. J. Chem. Theory Comput. 2007, 3, 619– 627, DOI: 10.1021/ct600256s[ACS Full Text], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhtlekt73I&md5=936a42f8641fbf6ce95efc54918a9596The B(OH)-NH Analog Is a Surrogate for the Amide Bond (CO-NH) in Peptides: An ab Initio StudyMalde, Alpeshkumar K.; Khedkar, Santosh A.; Coutinho, Evans C.Journal of Chemical Theory and Computation (2007), 3 (2), 619-627CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)The conformational preferences of N-methyl-methylboronamide (NMB), a B(OH)-NH analog of the amide CO-NH in natural peptides, were studied at the Hartree-Fock; Becke's three-parameter exchange functional and the gradient-cor. functional of Lee, Yang, and Parr; and 2nd-order Moller-Plesset levels of theory with the 6-31+G* basis set. The min., saddle points, and rotation barriers on the potential energy surface of NMB were located and the energy barriers estd. Besides the global min., there are three local min. within 2.0 kcal mol-1 of the global min. characterized by specific ω and τ torsion values. The energy barriers for rotation about the ω angle are 16.4-18.8 kcal mol-1 and are a consequence of the double-bond character of the B-N bond as revealed by natural bond orbitals calcns. The ω angle and the ω rotation barrier are nearly the same as those seen in natural peptides. The τ rotation barriers (B-O bond) are relatively low because of the single-bond character of the B-O bond. Ala-BON, the Ala-dipeptide derived from NMB, was constructed as a model peptide to study the conformational preferences about the φ and ψ torsion angles. The study reveals a strong preference for α-helix, type-II β-turn, 2.27 ribbon, and antiparallel β-sheet conformations, and mirror images of both type-II β-turn and 2.27 ribbon motifs whose φ and ψ values fall in the disfavored regions of the Ramachandran map. Thus, the replacement of the carbonyl group by B-OH retains the geometry and barrier around the ω angle and induces a strong preference for regular secondary structure motifs and also structures with pos. φ values. This makes the B(OH)-NH analog an important surrogate for the peptide bond, with the addnl. advantage of stability to proteolytic enzymes.
- 304Ramesh, R.; Reddy, D. S. Quest for novel chemical entities through incorporation of silicon in drug scaffolds. J. Med. Chem. 2018, 61, 3779– 3798, DOI: 10.1021/acs.jmedchem.7b00718[ACS Full Text], [CAS], Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1KnsbvM&md5=fa3da0fddb955d156d410eb68030e78aQuest for Novel Chemical Entities through Incorporation of Silicon in Drug ScaffoldsRamesh, Remya; Reddy, D. SrinivasaJournal of Medicinal Chemistry (2018), 61 (9), 3779-3798CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In order to optimize a lead mol. for further development, bioisosteric replacements are generally adopted as one of the strategies. Silicon appears to be the right choice as a carbon isostere because of the similarity in chem. properties. Silicon can be strategically introduced in a mol. to modulate its druglike properties, providing medicinal chemists with an unconventional strategy for replacing a carbon atom. Silicon can also be introduced to replace other heteroatoms and can act as a surrogate of functional groups such as olefin and amide as well. The present Perspective focuses on the opportunities that silicon incorporation offers in drug discovery, with an emphasis on case studies where introduction of silicon has created a benefit over its analog. We have tried to highlight all the recent developments in the field and briefly discuss the challenges assocd. with them.
- 305Chen, C. A.; Sieburth, S. M.; Glekas, A.; Hewitt, G. W.; Trainor, G. L.; Erickson-Viitanen, S.; Garber, S. S.; Cordova, B.; Jeffry, S.; Klabe, R. M. Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV protease. Chem. Biol. 2001, 8, 1161– 1166, DOI: 10.1016/S1074-5521(01)00079-5[Crossref], [PubMed], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XisFai&md5=1a1c62fd91039e43f4f2f211811cdde4Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV proteaseChen, Chien-An; Sieburth, Scott McN.; Glekas, Athanasios; Hewitt, Gregory W.; Trainor, George L.; Erickson-Viitanen, Susan; Garber, Sena S.; Cordova, Beverly; Jeffry, Susan; Klabe, Ronald M.Chemistry & Biology (2001), 8 (12), 1161-1166CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Science Ltd.)Background: Silicon is the element most similar to carbon, and bioactive organosilanes have therefore been of longstanding interest. Design of bioactive organosilanes has often involved a systematic replacement of a bioactive mol.'s stable carbon atoms with silicon. Silanediols, which are best known as unstable precursors of the robust and ubiquitous silicone polymers, have the potential to mimic an unstable carbon, the hydrated carbonyl. As a bioisostere of the tetrahedral intermediate of amide hydrolysis, a silanediol could act as a transition state analog inhibitor of protease enzymes. Results: Silanediol analogs of a carbinol-based inhibitor of the HIV protease were prepd. as single enantiomers, with up to six stereogenic centers. As inhibitors of this aspartic protease, the silanediols were nearly equiv. to both their carbinol analogs and indinavir, a current treatment for AIDS, with low nanomolar Ki values. IC90 data from a cell culture assay mirrored the Ki data, demonstrating that the silanediols can also cross cell membranes and deliver their antiviral effects. Conclusions: In their first evaluation as inhibitors of an aspartic protease, silanediol peptidomimetics have been found to be nearly as potent as currently available pharmaceutical agents, in enzyme and cell protection assays. These neutral, cell-permeable transition state analogs therefore provide a novel foundation for the design of therapeutic agents.
- 306Madsen, A. S.; Kristensen, H. M. E.; Lanz, G.; Olsen, C. A. The effect of various zinc binding groups on inhibition of histone deacetylases 1–11. ChemMedChem 2014, 9, 614– 626, DOI: 10.1002/cmdc.201300433[Crossref], [PubMed], [CAS], Google Scholar306https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitVWjur3N&md5=4cc4f341ecb112034d26aeb668f3332fThe Effect of Various Zinc Binding Groups on Inhibition of Histone Deacetylases 1-11Madsen, Andreas S.; Kristensen, Helle M. E.; Lanz, Gyrithe; Olsen, Christian A.ChemMedChem (2014), 9 (3), 614-626CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Histone deacetylases (HDACs) have the ability to cleave the acetyl groups of ε-N-acetylated lysine residues in a variety of proteins. Given that human cells contain thousands of different acetylated lysine residues, HDACS may regulate a wide variety of processes including some implicated in conditions such as cancer and neurodegenerative disorders. Herein we report the synthesis and in vitro biochem. profiling of a series of compds., including known inhibitors as well as novel chemotypes, that incorporate putative new zinc binding domains. By evaluating the compd. collection against all 11 recombinant human HDACs, we found that the trifluoromethyl ketone functionality provides potent inhibition of all four subclasses of the Zn2+-dependent HDACs. Potent inhibition was obsd. with two different scaffolds, demonstrating the efficiency of the trifluoromethyl ketone moiety as a zinc binding motif. Interestingly, we also identified silanediol as a zinc binding group with potential for future development of non-hydroxamate class I and class IIb HDAC inhibitors.
- 307Slusarczyk, M.; Serpi, M.; Pertusati, F. Phosphoramidates and phosphonamidates (ProTides) with antiviral activity. Antivir. Chem. Chemother. 2018, 26, 1– 31, DOI: 10.1177/2040206618775243
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Abstract
Figure 1
Figure 1. Structures of selected clinically approved drug molecules containing an amide bond and their biological function.
Figure 2
Figure 2. Representative structures of the trans and cis amide mimics 1,4-disubstitued 1,2,3-triazole and 1,5-disubstitued 1,2,3-triazole respectively, highlighting their distancing and hydrogen bonding capabilities.
Figure 3
Figure 3. Replacement of the amide bond in RN-18 (12) with a 1,2,3-triazole moiety to afford compound 13 (1-2-methoxyphenyl)-4-(2-((4-nitrophenyl)thio)phenyl)-1H-1,2,3-triazole).
Scheme 1
Scheme 1. General Synthetic Pathway To Access Triazole Scaffold via Copper(I)-Catalyzed Azide–Alkyne Cycloaddition Click ChemistryFigure 4
Figure 4. Example of amide versus 1,2,3-triazole bioisosterism in vismodegib (17), a potent Hh signaling pathway inhibitor.
Figure 5
Figure 5. Molecular structures of highly potent D3-R ligands: 20, 21, 22 containing amide; 23, a 1,2,3-triazole analog.
Figure 6
Figure 6. 1,2,3-Triazole as an amide bond bioisostere in a TRPV1/CB1 antagonist.
Figure 7
Figure 7. Molecular structure of lead compound 26 and its bioisostere 27.
Figure 8
Figure 8. Structural transformation of parent compound 28 into 29 illustrating amide/triazole bioisosterism.
Figure 9
Figure 9. Replacement of an amide moiety with a 1,2,4-triazole: diazepam (30) to alprazolam (31).
Figure 10
Figure 10. Metabolic transformation of diazepam (30) into three active metabolites: desmethyldiazepam/nordazepam (32), oxazepam (33), and temazepam (34).
Scheme 2
Scheme 2. Synthesis of the Benzodiazepine Compound Alprazolam (31) from 7-Chloro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepine-2-thione (35)Figure 11
Figure 11. Different regioisomeric forms of the oxadiazole ring.
Figure 12
Figure 12. Amide bioisosteric replacement with an oxadiazole ring leading to a potent and selective γ-secretase inhibitor.
Scheme 3
Scheme 3. General Synthetic Route To Obtain the 1,2,4-Oxadiazole Moiety from an AmidoximeFigure 13
Figure 13. Structures of parent amide-containing α-lipoic acid analog 28 and its 1,2,4-oxadiazole bioisostere 40.
Figure 14
Figure 14. Structures of parent chroman analog 41 and its 1,2,4-oxadiazole bioisostere 42.
Figure 15
Figure 15. Structures of parent amides 43 and 44, potent mGlu7-NAMs and the 1,3,4-oxadiazole bioisostere 45.
Scheme 4
Scheme 4. Synthetic Preparation of 45, a Potent and Selective mGlu7-NAMFigure 16
Figure 16. Structural optimization in the development of potent DPP-4 inhibitors to treat type 2 diabetes mellitus.
Scheme 5
Scheme 5. Synthetic Preparation of 50 and 51, Potent DPP InhibitorsFigure 17
Figure 17. Lead optimization journey to discover a potent and orally bioavailable DGAT-1 inhibitor.
Scheme 6
Scheme 6. General Synthetic Route for Preparing 1,3,4-Oxadiazole from DiacylhydrazineFigure 18
Figure 18. Bioisosteric amide replacement via 1,3,4-oxadiazole (65) and 1,2,4-oxadiazole (66) in a series of CB2 receptor ligands.
Figure 19
Figure 19. Structures of diazepam and the imidazole-containing analog midazolam.
Scheme 7
Scheme 7. One-Pot Synthesis of Midazolam, 67, a Short Acting BenzodiazepineFigure 20
Figure 20. Lead optimization journey of telcagepant (72) to discover 77, a potent and orally bioavailable CGRP antagonist.
Scheme 8
Scheme 8. Synthetic Route for Compound 77Figure 21
Figure 21. Structures of 80, 81, and imidazole bioisostere 82, potent HIV-1 integrase inhibitors.
Figure 22
Figure 22. Binding patterns of 81 and 82 into the active sites of PFV integrase (3S3N) wild-type (A) and Q148H/G140S mutant (B). Reproduced with permission from Bioorganic & Medicinal Chemistry Letters (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry-letters), Volume 30, 126784,
Peese, K. M.; Naidu, B. N.; Patel, M.; Li, C.; Langley, D. R.; Terry, B.; Protack, T.; Gali, V.; Lin, Z.; Samanta, H. K.; Zheng, M.; Jenkins, S.; Dicker, I. B.; Krystal, M. R.; Meanwell, N. A.; Walker, M. A. , Heterocycle amide isosteres: an approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors.(130) Copyright 2020 Elsevier.Scheme 9
Scheme 9. Synthetic Route To Access Imidazole Pyrimidinedione-Containing Derivative 82Figure 23
Figure 23. Bioisosteric replacement of the amide functional group in the identification of potent SCD1 inhibitors.
Scheme 10
Scheme 10. Synthetic Route for Compound 88Figure 24
Figure 24. Structure of 92 and its bioisostere 93, potent PAD inhibitors.
Scheme 11
Scheme 11. Synthetic Route To Access the Biphenyl Tetrazole tert-Butyl Cl-amidine-Containing PAD Inhibitor 93Figure 25
Figure 25. Structures of LA amide–dopamine conjugate 96 and its tetrazole containing bioisostere 97.
Scheme 12
Scheme 12. General Synthetic Route To Access Tetrazole, Nonclassical Amide BioisostereFigure 26
Figure 26. Molecular structures of parent LA-amide analog 28 and its tetrazole bioisostere 100.
Figure 27
Figure 27. Amide bond bioisosteric modification in 101 with a tetrazole functionality (102).
Figure 28
Figure 28. Oak Ridge thermal ellipsoid plots of 101 (A) and 102 (B). Reproduced with permission from European Journal of Medicinal Chemistry (https://www.sciencedirect.com/journal/european-journal-of-medicinal-chemistry), Volume 84, pp 200–205,
Beinat, C.; Reekie, T.; Hibbs, D.; Xie, T.; Olson, T. T.; Xiao, Y.; Harvey, A.; O’Connor, S.; Coles, C.; Tsanaktsidis, J.; Kassiou, M. , Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333.(149) Copyright 2014 Elsevier.Figure 29
Figure 29. Bioisosteric replacement of amide (103 and 104) with pyrazole (105 and 106) to discover potent PrCP inhibitors.
Figure 30
Figure 30. Amide versus thiadiazole bioisosterism in search of potent CB1 agonist.
Figure 31
Figure 31. Superimposition modeling image of 107 (green) and 111 (orange). Reproduced with permission from Bioorganic & Medicinal Chemistry Letters (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry-letters), Volume 21, pp 506–509,
Morrison, A. J.; Adam, J. M.; Baker, J. A.; Campbell, R. A.; Clark, J. K.; Cottney, J. E.; Deehan, M.; Easson, A. M.; Fields, R.; Francis, S.; Jeremiah, F.; Keddie, N.; Kiyoi, T.; McArthur, D. R.; Meyer, K.; Ratcliffe, P. D.; Schulz, J.; Wishart, G.; Yoshiizumi, K. , Design, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptor.(161) Copyright 2011 Elsevier.Figure 32
Figure 32. General structure (112) showing the molecular template for designing MMP inhibitors, isosteric replacement of the C-terminal amide bond in 113 with 3-acyl indole (114), and the structure of marimastat, (115), a broad-spectrum MMP inhibitor.
Scheme 13
Scheme 13. Synthesis of Indole Bioisostere 114, a Potent MMP InhibitorFigure 33
Figure 33. Molecular structures of the parent amide 119 and pyrazine (120), thiazole (121), and pyridine (122) bioisosteres.
Scheme 14
Scheme 14. Synthetic Route for Obtaining the Pyrazine Bioisostere 120, a Potent A2A Receptor AntagonistFigure 34
Figure 34. Structures of lead TYR2 inhibitor 125 and its optimized analogs 126–128.
Scheme 15
Scheme 15. Synthetic Route To Obtain Compound 128, a Potent TYR2 InhibitorFigure 35
Figure 35. Bioisosteric replacement of the amide within 132, with diketopiperazine (133, 134, and 135), to develop potent dopamine D2 receptor modulators.
Scheme 16
Scheme 16. Diketopiperazine Bioisostere Synthesis from l-Proline To Obtain Compound 134Figure 36
Figure 36. Structures of an amide-containing baccharin analog 138, a potent but low selective AKR1C3 inhibitor, and 139, a potent and highly selective retroinverted amide bioisostere.
Figure 37
Figure 37. Compound 139 docked within the active site of AKR1C3 (gray, PDB code 3UG8): strong predicted hydrogen bond (green dotted line) and weak predicted hydrogen bond (white dotted line). Reproduced with permission from Journal of Medicinal Chemistry,(183) Copyright 2019 American Chemical Society.
Scheme 17
Scheme 17. Synthetic Route To Access the Potent and Highly Selective AKR1C3 Inhibitor 139Figure 38
Figure 38. Structures of the parent amide 143 and the reverse amide bioisosteres 144 and 145, MTR ligands.
Scheme 18
Scheme 18. Synthetic Preparation of the Melatonin-Based Compounds 144 and 145Figure 39
Figure 39. Structures of parent amide 147, urea bioisosteres 148, 149, and 150, and 151, a potent urea ACAT inhibitor.
Scheme 19
Scheme 19. General Synthetic Route To Prepare Urea Bioisostere via IsocyanateFigure 40
Figure 40. Structures of DSG (155) and bioisosteric analogs.
Scheme 20
Scheme 20. Synthetic Procedure To Access 158, a Potent ImmunosuppressorFigure 41
Figure 41. Structures of lead compound 161 for anti-human cytomegalovirus (HCMV) and 2′-isopropoxyurea bioisostere 162.
Figure 42
Figure 42. Structures of 163, B13, a ceramide analog tested for in vitro cytotoxicity against five human tumor cell lines, and 164, a more potent urea bioisostere.
Figure 43
Figure 43. Antitrypanosomal agent 165, an amide derivative, was further optimized to urea derivatives 166 and 167.
Scheme 21
Scheme 21. Synthesis of 167, a Novel and Potential Drug for Human African TrypanosomiasisFigure 44
Figure 44. Structures of the amide (169) and urea (171) bioisostere derivatives of the triazole-based Escherichia coli PDHc-E1 inhibitor 169.
Figure 45
Figure 45. Graphical representation of the binding modes of 170 (A) and 171 (B) into the active site of E. coli PDHc-E1 displayed in ribbon. Ligands and residues are depicted by stick, while the hydrogen and coordination bonds are shown with dashed lines (green). Reproduced with permission from Bioorganic & Medicinal Chemistry (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry), Volume 22, pp 3180–3186,
He, J. B.; Ren, Y. L.; Sun, Q. S.; You, G. Y.; Zhang, L.; Zou, P.; Feng, L. L.; Wan, J.; He, H. W. , Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors.(222) Copyright 2014 Elsevier.Scheme 22
Scheme 22. Synthetic Route To Access the Potent Urea Derivative 171, an E. coli PDHc-E1 InhibitorFigure 46
Figure 46. Potent HIV protease inhibitors incorporating carbamate bioisosteres.
Scheme 23
Scheme 23. Synthetic Route To Access 3-(S)-Tetrahydrofuranylurethane-Containing Analog 176, a Potent HIV-1 Protease InhibitorFigure 47
Figure 47. Structures of parent amide 178, a γ-secretase inhibitor, and potent carbamate-based derivatives 179 and 180 for the treatment of AD.
Scheme 24
Scheme 24. Synthetic Route To Access the Dibenzazepinone-Based γ-Secretase Inhibitor 180Figure 48
Figure 48. Replacement of the amide bond in 182 with a carbamate moiety to afford compound 183, novel SP1–7 analogs as potential therapeutic agents for neuropathic pain.
Scheme 25
Scheme 25. Synthetic Route To a Carbamate-Based Dipeptide SP1–7 Analog (183)Figure 49
Figure 49. Amidine as a bioisostere of the amide functionality in VLA-4 antagonists.
Scheme 26
Scheme 26. Synthetic Route To Access Amidine Derivatives as VLA-4 AntagonistsFigure 50
Figure 50. Anthranilic acid lead 190, advanced lead 191, and alternative thioamide bioisostere 192 as antibacterial agents.
Scheme 27
Scheme 27. Synthetic Route To Access Thioamide 192Figure 51
Figure 51. Molecular structures of natural 194 and bioisosteric Ψ[CH(CF3)NH]Gly 195 and 196 peptides and (S,S) [NHCH(CF3)]-retro-thiorphan diastereomer 197.
Scheme 28
Scheme 28. Synthesis Route To Access Ψ[NHCH(CF3)]-retro-thiorphan 197Figure 52
Figure 52. Structures of 200 a reversible dipeptide inhibitor of cathepsin K, 201 a neutral cathepsin K inhibitor, and 202 a potent cathepsin K inhibitor containing the trifluoroethylamine bioisostere.
Scheme 29
Scheme 29. General Synthetic Route To Generate Trifluoroethylamine Bioisostere via a Trifluoroacetaldehyde Ethyl HemiacetalFigure 53
Figure 53. Structures of 205, a potent hepatitis C virus (HCV) NS3 protease inhibitor, and trifluoromethylated-containing cathepsin S inhibitors 206 and 207.
Figure 54
Figure 54. Structures of 208, an amide-based BACE-1 inhibitor, and CF3-cyclopropane bioisostere BACE-1 inhibitor 209.
Scheme 30
Scheme 30. Synthetic Route To Access Compound 209, a BACE-1 InhibitorFigure 55
Figure 55. Structures of parent malonamide 212 and selective and potent VEGFR2 inhibitor 213.
Figure 56
Figure 56. Structures of amide 163 and an aromatic sulfonamido ceramide bioisostere with more potent cytotoxic activity.
Scheme 31
Scheme 31. Synthetic Route To Access the Aromatic Alkyl Sulfonamido Ceramide Analog 214Figure 57
Figure 57. Phenoxyphenyl farnesylcysteine 217 and sulfonamide-modified farnesylcysteine (SMFC) analog 218, as hIcmt inhibitors.
Scheme 32
Scheme 32. General Synthetic Procedure To Obtain Sulfonamide BioisostereFigure 58
Figure 58. Capsaicin (24) and step by step development of novel capsaicin-like bioisosteric analogs 222–226.
Figure 59
Figure 59. Novel irreversible HIV-1 protease inhibitors encompassing sulfonamide and sulfone as amide bioisosteres.
Figure 60
Figure 60. Non-nucleoside NS5B inhibitors (except 233), containing the phosphonamidate group as an amide bioisostere (233, 234, and 235).
Figure 61
Figure 61. Ribbon structure of NS5B HCV viral polymerase. Reproduced with permission from Bioorganic & Medicinal Chemistry Letters (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry-letters), Volume 26, pp 4536–4541,
Pierra Rouviere, C.; Amador, A.; Badaroux, E.; Convard, T.; Da Costa, D.; Dukhan, D.; Griffe, L.; Griffon, J. F.; LaColla, M.; Leroy, F.; Liuzzi, M.; Loi, A. G.; McCarville, J.; Mascia, V.; Milhau, J.; Onidi, L.; Paparin, J. L.; Rahali, R.; Sais, E.; Seifer, M.; Surleraux, D.; Standring, D.; Dousson, C. , Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase.(259) Copyright 2016 Elsevier.Figure 62
Figure 62. Cocrystallization image of 235 complexed with the viral NS5B (PDB code 5CZB). Reproduced with permission from Bioorganic & Medicinal Chemistry Letters (https://www.sciencedirect.com/journal/bioorganic-and-medicinal-chemistry-letters), Volume 26, pp 4536–4541,
Pierra Rouviere, C.; Amador, A.; Badaroux, E.; Convard, T.; Da Costa, D.; Dukhan, D.; Griffe, L.; Griffon, J. F.; LaColla, M.; Leroy, F.; Liuzzi, M.; Loi, A. G.; McCarville, J.; Mascia, V.; Milhau, J.; Onidi, L.; Paparin, J. L.; Rahali, R.; Sais, E.; Seifer, M.; Surleraux, D.; Standring, D.; Dousson, C. , Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase.(259) Copyright 2016 Elsevier.Scheme 33
Scheme 33. Synthetic Route To Access 235Figure 63
Figure 63. Structures of peptide 238 and analogs in which the amide bond was replaced by an ester 239 or N-methylamide bond 240.
Figure 64
Figure 64. Amide to trans olefin bioisosteric replacement leading to the clinical candidate 242.
Scheme 34
Scheme 34. Synthetic Route To Access 242, a Non-Nucleoside HCV NS5B Polymerase InhibitorFigure 65
Figure 65. Example of the replacement of a central amide of an azaoxindole derivative (244) with an E-alkene moiety 245.
Scheme 35
Scheme 35. General Synthetic Route To Access Alkene BioisosteresFigure 66
Figure 66. Structural modification of an amide linker in 249 to an E-alkene in 250 that joins A and B rings.
Scheme 36
Scheme 36. General Synthesis of E-Alkene Bioisosteres from Respective AldehydeFigure 67
Figure 67. Molecular structures of amylin (20–29) 254 and its modified bioisosteric analogs.
Scheme 37
Scheme 37. Solid Phase Synthesis of an Alkene Dipeptide (255) and Alkene Dipeptidosulfonamide Isostere (256)Figure 68
Figure 68. Distamycin (262) and its bioisosteric analogs.
Figure 69
Figure 69. Amino acid sequences of bombesin (266), pseudopeptide 267, and E-alkene isostere 268.
Figure 70
Figure 70. Graphical representation of the modification of peptide backbone from an amide to E-olefin, which is neither a hydrogen bond donor nor acceptor.
Figure 71
Figure 71. Bioisosteric replacement of amide linkages from parent CCK peptides 271 and 272 to develop E-alkene isostere 273, a potent CCK-B receptor ligand.
Scheme 38
Scheme 38. Synthetic Route Showing the Peptide Coupling of the Dipeptide Isostere with CCK Fragment To Obtain Target Pseudopeptide 273Figure 72
Figure 72. Bioisosteric replacement of an amide bond at the Tyr1-Gly2 position in 238 with a fluoroalkene to produce 275 and a trifluoroethylamine moiety to produce (S)-276 and (R)-277.
Scheme 39
Scheme 39. Synthetic Route To Access Leu-enkephalin Analog 275Figure 73
Figure 73. Structures of the parent peptide 238 and its fluoroalkene isostere 283.
Scheme 40
Scheme 40. Synthetic Pathway To Obtain the Fluoroalkene Peptidomimetic Compound 283Figure 74
Figure 74. Bioisosteric replacement of the amide function in daclatasvir, 290, with a fluoro-olefin moiety to yield 291.
Scheme 41
Scheme 41. Diastereoselective Synthesis of Fluoro-olefin Analog 291 by Chang and Co-workersFigure 75
Figure 75. Inhibitor of Rho/MLK1 transcriptional pathway 301 and analogs with amide bioisosteric replacements 302 and 303.
Scheme 42
Scheme 42. Synthetic Access To Amide Bioisostere Analog 303 of a Rho/MLK1 Transcriptional Pathway Inhibitor 301Figure 76
Figure 76. Trisubstituted acylhydrazine as a tertiary amide bioisostere.
Scheme 43
Scheme 43. Synthetic Route To Access 308, a HCV NS5B Thumb Site II InhibitorReferences
ARTICLE SECTIONSThis article references 307 other publications.
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- 12Lima, L. M.; Barreiro, E. J. Bioisosterism: a useful strategy for molecular modification and drug design. Curr. Med. Chem. 2005, 12, 23– 49, DOI: 10.2174/0929867053363540[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjvVOrug%253D%253D&md5=4836e1d51143b240e357548b39f04251Bioisosterism: A useful strategy for molecular modification and drug designLima, Lidia Moreira; Barreiro, Eliezer J.Current Medicinal Chemistry (2005), 12 (1), 23-49CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)This review aims to demonstrate the role of bioisosterism in rational drug design as well as in the mol. modification and optimization process aiming to improve pharmacodynamic and pharmacokinetic properties of lead compds.
- 13Langmuir, I. Isomorphism, isosterism and covalence. J. Am. Chem. Soc. 1919, 41, 1543– 1559, DOI: 10.1021/ja02231a009[ACS Full Text], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaC1MXhtlamuw%253D%253D&md5=490a744bcbdd636dfa4ae48e9555b14cIsomorphism, isosterism and covalenceLangmuir, IrvingJournal of the American Chemical Society (1919), 41 (), 1543-59CODEN: JACSAT; ISSN:0002-7863.cf. C. A. 3, 1554. In compds. other than those of C the number of electron pairs held in common is not always the same as the number of valence bonds that have usually been assumed; thence it is proposed that the number of pairs of electrons which any atom shares with adjacent atoms be called the covalence of the atom. Pairs of compds. such as CO2 and N2O or CO and N2 which show extraordinary agreement in physical properties and which (according to the octet theory) have the same number and arrangement of electrons in the mol. are called isosteric: compds. or isosteres. The term is applicable not only to mols. but to radicals or groups of atoms which hold pairs of electrons in common. Thus a mol. and an ion may be isosteres, e. g., Ne, Na+ Mg++, Al+++, O- and F- are all isosteric with one another. A table of 21 types of isosterism is given. When isosteric mols. are also isoelectric, that is when they have the same total charge on the comolecule, all of their phys. properties should be closely similar. (Comolecules are groups of atoms held together by pairs of electrons shared by adjacent atoms.) This is shown to be true for cyanate and azide ions and the compds. derived from them. No direct comparison can be made of the phys. properties of isosteres having different electric charges. Thus Na salts do not resemble Ne, although Na+ is isosteric with Ne. But another type of comparison can be made as to the actual isosterism of comolecules with different charges. For example, A and N2 resemble each other closely; therefore chloride ion, isosteric with A, should have a close resemblance to the cyanide ion which is isosteric with N2. The similarity of chlorides and cynides is thus directly correlated with that between A and N. A similar close relationship between K salts and NH4 salts can be derived, since A is an isostere of K+ and CH4 is an isostere of NH4+, while the 2 gases are alike in all their physical properties. Since the Na+ and F- ions are isosteric, while Mg++ and O-- are also isosteric, MgO and NaF should be identical in crystal structure. Both are cubic, and they have the same crystal structure according to the X-ray spectra, except that the atoms are drawn closer together by the greater forces in MgO. Thus they should be looked upon as isomorphous. Other similar pairs are MgF2 and Na2O, KCl and CaS, K2S and CaCl2, Cu2S and ZnCl2, KNO3 and SrCO3, KClO4, and SrSO4, etc. Crystalline form depends on structure as given by the octet theory, which gives a true picture of the constitutions of cryst. solids. The following conclusions are justified: The covalence of Na, K, Cl (in chlorides) is zero; the covalence of the central atom is 4 in nitrates, carbonates, sulfates, perchlorates, phosphates, permanganates, chromates, selenates, arsenates, borofluorides, etc.; carbonates and sulfides are not isomorphous, the covalence of the central atom being 4 and 3, resp.; nitrates and chlorates are not isomorphous, the covalency of the chlorine being 3 in chlorates. The applicability of the octet theory to complex inorg. compds. receives further confirmation by its ability to explain such cases of isomorphism. as between Na2BeF4 and MnCl2.4H2O, K2SO4 and ZnI2.4NH3, K2SnCl4.2H2O and K2FeCl5.H2O, NaAlSi3O8 and CaAl2Si2O8.
- 14Papadatos, G.; Brown, N. In silico applications of bioisosterism in contemporary medicinal chemistry practice. WIREs Comput. Mol. Sci. 2013, 3, 339– 354, DOI: 10.1002/wcms.1148[Crossref], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtV2ntrfN&md5=70c576ff3ad5c44f5b0394e6a4ef881bIn silico applications of bioisosterism in contemporary medicinal chemistry practicePapadatos, George; Brown, NathanWiley Interdisciplinary Reviews: Computational Molecular Science (2013), 3 (4), 339-354CODEN: WIRCAH; ISSN:1759-0884. (Wiley-Blackwell)A review. Bioisosterism is a key concept in medicinal chem., as it allows medicinal chemists to interchange structural fragments without significant perturbation in biol. activity. Not surprisingly, given the vast amt. of bioactivity data and chemoinformatics resources now available, there has been a significant surge in the no. of computational approaches available to mine and identify bioisosteric replacements for fragments of bioactive compds. Such methods have certainly provided medicinal chemists with a diverse arsenal of inhouse, com., and academic tools and interfaces to aid in the optimization across a no. of end points such as bioactivity; selectivity; and absorption, distribution, metab., excretion, and toxicity properties for effective and efficient drug design. These in silico bioisosteric replacement mining approaches can generally be divided into two categories, namely ligand based and structure based. The approaches of the former category use information that is derived from ligands, whereas the latter category requires knowledge of the biol. target, as well as specific knowledge of the interactions between ligand and target in the binding pocket. Ligand-based methodologies are also typically divided into similarity-based and database mining (or knowledge-based) approaches. In general, the former provide an assessment of putative bioisosteric fragments and substructures, in terms of mol. topol. and descriptors, whereas the latter ext. structural transformations from large chem. repositories and assoc. them with the induced change in biol. or any other property of interest. Following systematic retrospective studies, a large no. of nonclassical bioisosteric equiv. have been reported in the literature.
- 15Dick, A.; Cocklin, S. Bioisosteric replacement as a tool in anti-HIV drug design. Pharmaceuticals 2020, 13, 36, DOI: 10.3390/ph13030036[Crossref], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvVeisLvL&md5=98a5afb666286670b9f6a7a994861924Bioisosteric replacement as a tool in Anti-HIV drug designDick, Alexej; Cocklin, SimonPharmaceuticals (2020), 13 (3), 36CODEN: PHARH2; ISSN:1424-8247. (MDPI AG)A review. Bioisosteric replacement is a powerful tool for modulating the drug-like properties, toxicity, and chem. space of exptl. therapeutics. In this review, we focus on selected cases where bioisosteric replacement and scaffold hopping have been used in the development of new anti-HIV-1 therapeutics. Moreover, we cover field-based, computational methodologies for bioisosteric replacement, using studies from our group as an example. It is our hope that this review will serve to highlight the utility and potential of bioisosteric replacement in the continuing search for new and improved anti-HIV drugs.
- 16Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem. 2011, 54, 2529– 2591, DOI: 10.1021/jm1013693[ACS Full Text], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjsVCnu7o%253D&md5=0637ab60c379bef535f3f709b26f3582Synopsis of Some Recent Tactical Application of Bioisosteres in Drug DesignMeanwell, Nicholas A.Journal of Medicinal Chemistry (2011), 54 (8), 2529-2591CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering phys. properties, reducing or redirecting metab., eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compd. optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examd. are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chem. setting has been adopted by this community.
- 17Meanwell, N. A. The Influence of Bioisosteres in Drug Design: Tactical Applications to Address Developability Problems. In Tactics in Contemporary Drug Design; Meanwell, N. A., Ed.; Springer: Berlin, 2015; pp 283– 381.
- 18Herr, R. J. 5-Substituted-1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methods. Bioorg. Med. Chem. 2002, 10, 3379– 3393, DOI: 10.1016/S0968-0896(02)00239-0[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xms12jurY%253D&md5=a7892c9a0eabe9a1b6c9ead0a3327a2e5-Substituted 1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methodsHerr, R. JasonBioorganic & Medicinal Chemistry (2002), 10 (11), 3379-3393CODEN: BMECEP; ISSN:0968-0896. (Elsevier Science Ltd.)A review on the medicinal chem. of tetrazolic acids highlighting some examples of tetrazole-contg. drug substances in the current literature. 5-Substituted 1H-tetrazoles (RCN4H) are often used as metab.-resistant isosteric replacements for carboxylic acids (RCO2H) in SAR-driven medicinal chem. analog syntheses. A survey of representative literature procedures for the prepn. of 5-substituted 1H-tetrazoles, focusing on prepns. from aryl and alkyl nitriles, is presented in sections by generalized synthetic methods.
- 19Bonandi, E.; Christodoulou, M. S.; Fumagalli, G.; Perdicchia, D.; Rastelli, G.; Passarella, D. The 1,2,3-triazole ring as a bioisostere in medicinal chemistry. Drug Discovery Today 2017, 22, 1572– 1581, DOI: 10.1016/j.drudis.2017.05.014[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFCmurrK&md5=0ea3588d22d266e5eed9f401c887b838The 1,2,3-triazole ring as a bioisostere in medicinal chemistryBonandi, Elisa; Christodoulou, Michael S.; Fumagalli, Gaia; Perdicchia, Dario; Rastelli, Giulio; Passarella, DanieleDrug Discovery Today (2017), 22 (10), 1572-1581CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)1,2,3-Triazole is a well-known scaffold that has a widespread occurrence in different compds. characterized by several bioactivities, such as antimicrobial, antiviral, and antitumor effects. Moreover, the structural features of 1,2,3-triazole enable it to mimic different functional groups, justifying its wide use as a bioisostere for the synthesis of new active mols. Here, we provide an overview of the 1,2,3-triazole ring as a bioisostere for the design of drug analogs, highlighting relevant recent examples.
- 20Lenci, E.; Trabocchi, A. Peptidomimetic toolbox for drug discovery. Chem. Soc. Rev. 2020, 49, 3262– 3277, DOI: 10.1039/D0CS00102C[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsFSnuro%253D&md5=6624d8fd44e8af567591e70815a649f6Peptidomimetic toolbox for drug discoveryLenci, Elena; Trabocchi, AndreaChemical Society Reviews (2020), 49 (11), 3262-3277CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. The art of transforming peptides into drug leads is still a dynamic and fertile field in medicinal chem. and drug discovery. Peptidomimetics can respond to peptide limitations by displaying higher metabolic stability, good bioavailability and enhanced receptor affinity and selectivity. Various synthetic strategies have been developed over the years in order to modulate the conformational flexibility and the peptide character of peptidomimetic compds. This tutorial review aims to outline useful tools towards peptidomimetic design, spanning from local modifications, global restrictions and the use of secondary structure mimetics. Selected successful examples of each approach are presented to document the relevance of peptidomimetics in drug discovery.
- 21Fosgerau, K.; Hoffmann, T. Peptide therapeutics: current status and future directions. Drug Discovery Today 2015, 20, 122– 128, DOI: 10.1016/j.drudis.2014.10.003[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsl2ksLnM&md5=f6b74aaa4e3fdb317b091b0450f3618aPeptide therapeutics: current status and future directionsFosgerau, Keld; Hoffmann, TorstenDrug Discovery Today (2015), 20 (1), 122-128CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. Peptides are recognized for being highly selective and efficacious and, at the same time, relatively safe and well tolerated. Consequently, there is an increased interest in peptides in pharmaceutical research and development (R&D), and approx. 140 peptide therapeutics are currently being evaluated in clin. trials. Given that the low-hanging fruits in the form of obvious peptide targets have already been picked, it has now become necessary to explore new routes beyond traditional peptide design. Examples of such approaches are multifunctional and cell penetrating peptides, as well as peptide drug conjugates. Here, we discuss the current status, strengths, and weaknesses of peptides as medicines and the emerging new opportunities in peptide drug design and development.
- 22Henninot, A.; Collins, J. C.; Nuss, J. M. The current state of peptide drug discovery: back to the future?. J. Med. Chem. 2018, 61, 1382– 1414, DOI: 10.1021/acs.jmedchem.7b00318[ACS Full Text], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1ansLbM&md5=825f15ed57fceaa1226f57be696c639eThe Current State of Peptide Drug Discovery: Back to the Future?Henninot, Antoine; Collins, James C.; Nuss, John M.Journal of Medicinal Chemistry (2018), 61 (4), 1382-1414CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Over the last decade, peptide drug discovery has experienced a revival of interest and scientific momentum, as the pharmaceutical industry has come to appreciate the role that peptide therapeutics can play in addressing unmet medical needs, and how this class of compds. can be an excellent complement or even preferable alternative to small mol. and biol. therapeutics. In this perspective we give a concise description of the recent progress in peptide drug discovery in a holistic manner, highlighting enabling technol. advances affecting nearly every aspect of this field: from lead discovery, to synthesis and optimization, to peptide drug delivery. An emphasis is placed on describing research efforts to overcome the inherent weaknesses of peptide drugs, in particular their poor pharmacokinetic properties, and how these efforts have been crit. to the discovery, design and subsequent development of novel therapeutics.
- 23Lau, J. L.; Dunn, M. K. Therapeutic peptides: historical perspectives, current development trends, and future directions. Bioorg. Med. Chem. 2018, 26, 2700– 2707, DOI: 10.1016/j.bmc.2017.06.052[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFygt7jP&md5=c4dc775ee302737cfc5080ea3f1c8c74Therapeutic peptides: Historical perspectives, current development trends, and future directionsLau, Jolene L.; Dunn, Michael K.Bioorganic & Medicinal Chemistry (2018), 26 (10), 2700-2707CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)A review. Peptide therapeutics have played a notable role in medical practice since the advent of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United States and other major markets, and peptides continue to enter clin. development at a steady pace. Peptide drug discovery has diversified beyond its traditional focus on endogenous human peptides to include a broader range of structures identified from other natural sources or through medicinal chem. efforts. The authors maintain a comprehensive dataset on peptides that have entered human clin. studies that includes over 150 peptides in active development today. Here the authors provide an overview of the peptide therapeutic landscape, including historical perspectives, mol. characteristics, regulatory benchmarks, and a therapeutic area breakdown.
- 24Lee, A. C.; Harris, J. L.; Khanna, K. K.; Hong, J. H. A comprehensive review on current advances in peptide drug development and design. Int. J. Mol. Sci. 2019, 20, 2383, DOI: 10.3390/ijms20102383[Crossref], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXosVGiuw%253D%253D&md5=344174f95cb22357d0b92d797874d81bA comprehensive review on current advances in peptide drug development and designLee, Andy Ch-Lung; Harris, Janelle Louise; Khanna, Kum Kum; Hong, Ji-HongInternational Journal of Molecular Sciences (2019), 20 (10), 2383/1-2383/21CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)Protein-protein interactions (PPIs) execute many fundamental cellular functions and have served as prime drug targets over the last two decades. Interfering intracellular PPIs with small mols. has been extremely difficult for larger or flat binding sites, as antibodies cannot cross the cell membrane to reach such target sites. In recent years, peptides smaller size and balance of conformational rigidity and flexibility have made them promising candidates for targeting challenging binding interfaces with satisfactory binding affinity and specificity. Deciphering and characterizing peptide-protein recognition mechanisms is thus central for the invention of peptide-based strategies to interfere with endogenous protein interactions, or improvement of the binding affinity and specificity of existing approaches. Importantly, a variety of computation-aided rational designs for peptide therapeutics have been developed, which aim to deliver comprehensive docking for peptide-protein interaction interfaces. Over 60 peptides have been approved and administrated globally in clinics. Despite this, advances in various docking models are only on the merge of making their contribution to peptide drug development. In this review, we provide (i) a holistic overview of peptide drug development and the fundamental technologies utilized to date, and (ii) an updated review on key developments of computational modeling of peptide-protein interactions (PepPIs) with an aim to assist exptl. biologists exploit suitable docking methods to advance peptide interfering strategies against PPIs.
- 25He, R.; Finan, B.; Mayer, J. P.; DiMarchi, R. D. Peptide conjugates with small molecules designed to enhance efficacy and safety. Molecules 2019, 24, 1855, DOI: 10.3390/molecules24101855[Crossref], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFagtb%252FM&md5=da04d398164460a08977abcdcefdc230Peptide conjugates with small molecules designed to enhance efficacy and safetyHe, Rongjun; Finan, Brian; Mayer, John P.; DiMarchi, Richard D.Molecules (2019), 24 (10), 1855CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. Peptides constitute mol. diversity with unique mol. mechanisms of action that are proven indispensable in the management of many human diseases, but of only a mere fraction relative to more traditional small mol.-based medicines. The integration of these two therapeutic modalities o ers the potential to enhance and broaden pharmacol. while minimizing dose-dependent toxicol. This review summarizes numerous advances in drug design, synthesis and development that provide direction for next-generation research endeavors in this field. Medicinal studies in this area have largely focused upon the application of peptides to selectively enhance small mol. cytotoxicity to more effectively treat multiple oncol. diseases. To a lesser and steadily emerging extent peptides are being therapeutically employed to complement and diversify the pharmacol. of small mol. drugs in diseases other than just cancer. No matter the disease, the purpose of the mol. integration remains const. and it is to achieve superior therapeutic outcomes with diminished adverse effects. We review linker technol. and conjugation chemistries that have enabled integrated and targeted pharmacol. with controlled release. Finally, we offer our perspective on opportunities and obstacles in the field.
- 26Kaspar, A. A.; Reichert, J. M. Future directions for peptide therapeutics development. Drug Discovery Today 2013, 18, 807– 817, DOI: 10.1016/j.drudis.2013.05.011[Crossref], [PubMed], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpsV2ksbs%253D&md5=df04991ff869d0d85386254d378664ccFuture directions for peptide therapeutics developmentKaspar, Allan A.; Reichert, Janice M.Drug Discovery Today (2013), 18 (17-18), 807-817CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. The notable expansion of peptide therapeutics development in the late 1990s and the 2000s led to an unprecedented no. of marketing approvals in 2012 and has provided a robust pipeline that should deliver numerous approvals during the remainder of the 2010s. To document the current status of the pipeline, we collected data for peptide therapeutics in clin. studies and regulatory review, as well as those recently approved. In this Foundation review, we provide an overview of the pipeline, including therapeutic area and mol. targets, with a focus on glucagon-like peptide 1 receptor agonists. Areas for potential expansion, for example constrained peptides and peptide-drug conjugates, are profiled.
- 27Cramer, R. D.; Clark, R. D.; Patterson, D. E.; Ferguson, A. M. Bioisosterism as a molecular diversity descriptor: steric fields of single “topomeric” conformers. J. Med. Chem. 1996, 39, 3060– 3069, DOI: 10.1021/jm960291f[ACS Full Text], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xkt1alurw%253D&md5=599f03f9824679ca1ca4f762a1924e8dBioisosterism as a Molecular Diversity Descriptor: Steric Fields of Single "Topomeric" ConformersCramer, Richard D.; Clark, Robert D.; Patterson, David E.; Ferguson, Allan M.Journal of Medicinal Chemistry (1996), 39 (16), 3060-3069CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The comparative mol. field anal. steric field of a single "topomeric" conformer is introduced as a mol. diversity descriptor particularly useful for combinatorial chem. involving variations around a fixed "core". Using this new descriptor, 736 com. available thiols are divided into 231 bioisosteric clusters, whose compns. agree at least as well with medicinal chem. experience and intuition as do clusters derived from Tanimoto differences between 2D fragment occurrences. However, in practice topomeric steric fields complement 2D fingerprints, being the two most frequently useful descriptors yet found for neighborhood-based design of combinatorial libraries.
- 28Ertl, P. In silico identification of bioisosteric functional groups. Curr. Opin. Drug Discovery Dev. 2007, 10, 281– 288[PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmtVWlsrk%253D&md5=477b7ecaaf2a5323820f3b50c1559732In silico identification of bioisosteric functional groupsErtl, PeterCurrent Opinion in Drug Discovery & Development (2007), 10 (3), 281-288CODEN: CODDFF; ISSN:1367-6733. (Thomson Scientific)A review. Bioisosteric replacement is a std. technique that is used in medicinal chem. to design analogs of bioactive mols. with similar activity and with addnl. improved characteristics. However, successful bioisosteric design requires significant prior chem. knowledge, and the identification of a replacement group with an optimal balance of steric, hydrophobic, electronic and hydrogen-bonding properties that all influence ligand-receptor interactions usually requires a demanding procedure of trial and error. In this article, various methods that can help medicinal chemists to identify bioisosteric analogs are reviewed, beginning with classical techniques using exptl. group properties. Methods to find bioisosteric pairs based on the anal. of large mol. databases are discussed. Various descriptors to characterize properties of functional groups are described, and methods to identify bioisosteric replacement by conducting property similarity search are presented. Examples of tools that help chemists to navigate within the group functional property space are also provided.
- 29Devereux, M.; Popelier, P. L. A. In silico techniques for the identification of bioisosteric replacements for drug design. Curr. Top. Med. Chem. 2010, 10, 657– 668, DOI: 10.2174/156802610791111470[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlslSgsbo%253D&md5=86300aca3a8eebbe9df79c7a6c7be152In silico techniques for the identification of bioisosteric replacements for drug designDevereux, Mike; Popelier, Paul L. A.Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10 (6), 657-668CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)A review. This article provides an overview of the broad and increasingly varied selection of computational approaches available to find bioisosteric replacements for fragments of bioactive compds. The rapidly increasing no. and diversity of methods has provided medicinal chemists with a powerful range of com. and academic tools to aid in the optimization of lead compd. activity and ADMET properties for drug design. We discuss methods with fundamentally different philosophies, ranging from evaluation of similarity in a calcd. property space to cheminformatics anal. of pharmaceutical compd. databases. We also discuss the incorporation, within these methods, of a whole spectrum of exptl. and calcd. data to describe fragment chem. and compd. activity. Despite the growing sophistication of available techniques, there remains much scope for further development and esp. for deeper validation of the efficacy of different approaches in what seems set to remain an expanding field.
- 30Olesen, P. H. The use of bioisosteric groups in lead optimization. Curr. Opin. Drug Discovery Dev. 2001, 4, 471– 478[PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlsVKktbc%253D&md5=9798dc03c0dca889fcf94fe4fef7bb13The use of bioisosteric groups in lead optimizationOlesen, Preben H.Current Opinion in Drug Discovery & Development (2001), 4 (4), 471-478CODEN: CODDFF; ISSN:1367-6733. (PharmaPress Ltd.)A review with refs. It is now half a century since Friedman introduced the term bioisosterism for the similar biol. activity of structurally related compds. Since then, the concept has been used extensively and successfully in the optimization of lead compds. in drug discovery. The no. of chem. lead compds. has expanded enormously in recent years due to the expression of an increasing no. of recombinant proteins, and the screening of these new protein targets against a large no. of compds. in high-throughput screens. For the fine-tuning of lead compds. to obtain candidates suitable for clin. trials, which is in most circumstances still a tedious process, the use of bioisosteric replacement can be of significant value. This is esp. the case in optimizing for selectivity for a specific target and in improving the pharmacokinetic properties of lead compds. The use of bioisosteres in lead optimization is illustrated by some recent examples from the literature.
- 31Thornber, C. W. Isosterism and molecular modification in drug design. Chem. Soc. Rev. 1979, 8, 563– 580, DOI: 10.1039/cs9790800563[Crossref], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXktlKmsL0%253D&md5=25e8bd3c46affd25b72fbf87a44a3b27Isosterism and molecular modification in drug designThornber, C. W.Chemical Society Reviews (1979), 8 (4), 563-80CODEN: CSRVBR; ISSN:0306-0012.A review with 76 refs.
- 32Sun, S.; Jia, Q.; Zhang, Z. Applications of amide isosteres in medicinal chemistry. Bioorg. Med. Chem. Lett. 2019, 29, 2535– 2550, DOI: 10.1016/j.bmcl.2019.07.033[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFSrt7zE&md5=329e431db6b70c733130197e3828eb89Applications of amide isosteres in medicinal chemistrySun, Shaoyi; Jia, Qi; Zhang, ZaihuiBioorganic & Medicinal Chemistry Letters (2019), 29 (18), 2535-2550CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. Isosteric replacement of amide groups is a classic practice in medicinal chem. This digest highlights the applications of most commonly employed amide isosteres in drug design aiming at improving potency and selectivity, optimizing physicochem. and pharmacokinetic properties, eliminating or modifying toxicophores, as well as providing novel intellectual property of lead compds.
- 33Bachl, J.; Mayr, J.; Sayago, F. J.; Cativiela, C.; Díaz Díaz, D. Amide–triazole isosteric substitution for tuning self-assembly and incorporating new functions into soft supramolecular materials. Chem. Commun. 2015, 51, 5294– 5297, DOI: 10.1039/C4CC08593K[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitValurnF&md5=5827b04ade6463e7e5d061014e8d02f4Amide-triazole isosteric substitution for tuning self-assembly and incorporating new functions into soft supramolecular materialsBachl, Juergen; Mayr, Judith; Sayago, Francisco J.; Cativiela, Carlos; Diaz Diaz, DavidChemical Communications (Cambridge, United Kingdom) (2015), 51 (25), 5294-5297CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)The proof-of-concept for the modular synthesis of new functional soft gel materials based on amide-triazole isosteric replacement has been demonstrated. A coassembly approach of isosteric amino acid-based hydrogelators was fruitfully applied for fine-tuning the release of entrapped drugs.
- 34Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A. Click chemistry reactions in medicinal chemistry: applications of the 1,3-dipolar cycloaddition between azides and alkynes. Med. Res. Rev. 2008, 28, 278– 308, DOI: 10.1002/med.20107[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjsVerurg%253D&md5=ef565fc46c50047a6181e85711cb5c37Click chemistry reactions in medicinal chemistry: applications of the 1,3-dipolar cycloaddition between azides and alkynesTron, Gian Cesare; Pirali, Tracey; Billington, Richard A.; Canonico, Pier Luigi; Sorba, Giovanni; Genazzani, Armando A.Medicinal Research Reviews (2008), 28 (2), 278-308CODEN: MRREDD; ISSN:0198-6325. (John Wiley & Sons, Inc.)A review. In recent years, there has been an ever-increasing need for rapid reactions that meet the three main criteria of an ideal synthesis: efficiency, versatility, and selectivity. Such reactions would allow medicinal chem. to keep pace with the multitude of information derived from modern biol. screening techniques. The present review describes one of these reactions, the 1,3-dipolar cycloaddn. ("click-reaction") between azides and alkynes catalyzed by copper (I) salts. The simplicity of this reaction and the ease of purifn. of the resulting products have opened new opportunities in generating vast arrays of compds. with biol. potential. The present review will outline the accomplishments of this strategy achieved so far and outline some of medicinal chem. applications in which click-chem. might be relevant in the future.
- 35Hou, J.; Liu, X.; Shen, J.; Zhao, G.; Wang, P. G. The impact of click chemistry in medicinal chemistry. Expert Opin. Drug Discovery 2012, 7, 489– 501, DOI: 10.1517/17460441.2012.682725[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xns1SrtL0%253D&md5=6db4e8d966aec6a597971e3d9a2c605cThe impact of click chemistry in medicinal chemistryHou, Jingli; Liu, Xifang; Shen, Jie; Zhao, Guilong; Wang, Peng GeorgeExpert Opinion on Drug Discovery (2012), 7 (6), 489-501CODEN: EODDBX; ISSN:1746-0441. (Informa Healthcare)A review. Introduction: The copper(I)-catalyzed 1,3-dipolar cycloaddn. of alkynes and azides to form 1,2,3-triazoles is the most popular reaction in click chem. This reaction is also near-perfect, in terms of its robustness, due to the high degree of reliability and complete specificity. Furthermore, this reaction has been used increasingly in drug discovery, because the formed 1,2,3-triazole can act as both a bioisostere and a linker. Areas covered: This review provides an overview of a most important click reaction, 1,3-dipolar cycloaddns. of alkynes and azides, in the drug discovery.Expert opinion: Click chem. is a very powerful tool, in the drug discovery, because it is very efficient in the creation of compd. libraries through combinatorial methodol. However, the 1,2,3-triazole ring itself is not a commonly used pharmacophore and has rarely been found in marketed drugs, demonstrating that there are still some limitations during the use of 1,2,3-triazole in the mols. of drug candidates. Hopefully, in the next decade, we will witness the emergence of 1,2,3-triazole-bearing drugs on the market as this click reaction is used more and more widely in the drug discovery.
- 36Prasher, P.; Sharma, M. Tailored therapeutics based on 1,2,3-1H-triazoles: a mini review. MedChemComm 2019, 10, 1302– 1328, DOI: 10.1039/C9MD00218A[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpsVamt7g%253D&md5=4aab5704a66bbe69ee624a2b5280491bTailored therapeutics based on 1,2,3-1H-triazoles: a mini reviewPrasher, Parteek; Sharma, MousmeeMedChemComm (2019), 10 (8), 1302-1328CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Contemporary drug discovery approaches rely on library synthesis coupled with combinatorial methods and high-throughput screening to identify leads. However, due to the multitude of components involved, a majority of optimization techniques face persistent challenges related to the efficiency of synthetic processes and the purity of compd. libraries. These methods have recently found an upgradation as fragment-based approaches for target-guided synthesis of lead mols. with active involvement of their biol. target. The click chem. approach serves as a promising tool for tailoring the therapeutically relevant biomols. of interest, improving their bioavailability and bioactivity and redirecting them as efficacious drugs. 1,2,3-1H-Triazole nucleus, being a planar and biol. acceptable scaffold, plays a crucial role in the design of biomol. mimetics and tailor-made mols. with therapeutic relevance. This versatile scaffold also forms an integral part of the current fragment-based approaches for drug design, kinetic target guided synthesis and bioorthogonal methodologies.
- 37Chrysina, E. D.; Bokor, É.; Alexacou, K.-M.; Charavgi, M.-D.; Oikonomakos, G. N.; Zographos, S. E.; Leonidas, D. D.; Oikonomakos, N. G.; Somsák, L. Amide-1,2,3-triazole bioisosterism: the glycogen phosphorylase case. Tetrahedron: Asymmetry 2009, 20, 733– 740, DOI: 10.1016/j.tetasy.2009.03.021[Crossref], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtVeju74%253D&md5=99b5649d2eaeb32044b95945e816ae62Amide-1,2,3-triazole bioisosterism: the glycogen phosphorylase caseChrysina, Evangelia D.; Bokor, Eva; Alexacou, Kyra-Melinda; Charavgi, Maria-Despoina; Oikonomakos, George N.; Zographos, Spyros E.; Leonidas, Demetres D.; Oikonomakos, Nikos G.; Somsak, LaszloTetrahedron: Asymmetry (2009), 20 (6-8), 733-740CODEN: TASYE3; ISSN:0957-4166. (Elsevier Ltd.)Per-O-acetylated β-D-glucopyranosyl azide was transformed into an intermediate iminophosphorane by PMe3 which was then acylated to N-acyl-β-D-glucopyranosylamines. The same azide and substituted acetylenes gave 1-(β-D-glucopyranosyl)-4-substituted-1,2,3-triazoles in Cu(I)-catalyzed azide-alkyne cycloaddns. Deprotection of these products by the Zemplen method furnished β-D-Glcp-NHCO-R derivs. I (R = ph, 1-naphthyl, 2-naphthyl, CH2OH) as well as 1-(β-D-Glcp)-4-R-1,2,3-triazoles II (R = ph, 1-naphthyl, 2-naphthyl, CH2OH) which were evaluated as inhibitors of rabbit muscle glycogen phosphorylase b. Pairs of amides vs. triazoles with the same R group displayed similar inhibition consts. X-ray crystallog. studies on the enzyme-inhibitor complexes revealed high similarities in the binding of pairs with R = 2-naphthyl and hydroxymethyl, while for the R = Ph and 1-naphthyl compds. a different orientation of the arom. part and changes in the conformation of the 280s loop were obsd. By this study new examples of amide-1,2,3-triazole bioisosteric relationship have been provided.
- 38Angell, Y. L.; Burgess, K. Peptidomimetics via copper-catalyzed azide-alkyne cycloadditions. Chem. Soc. Rev. 2007, 36, 1674– 1689, DOI: 10.1039/b701444a[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsVKit78%253D&md5=0b4a29de9c62148ffe459efef31c3f35Peptidomimetics via copper-catalyzed azide-alkyne cycloadditionsAngell, Yu L.; Burgess, KevinChemical Society Reviews (2007), 36 (10), 1674-1689CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. This crit. review concerns the impact of copper-mediated alkyne-azide cycloaddns. on peptidomimetic studies. It discusses how this reaction has been used to insert triazoles into peptide chains, to link peptides to other functionalities (e.g. carbohydrates, polymers, and labels), and as a basis for evolution of peptidomimetics as pharmaceutical leads. This work will be of interest to those studying "Click reaction", peptidomimetic secondary structure and function, and to medicinal chemists.
- 39Nathans, R.; Cao, H.; Sharova, N.; Ali, A.; Sharkey, M.; Stranska, R.; Stevenson, M.; Rana, T. M. Small-molecule inhibition of HIV-1 Vif. Nat. Biotechnol. 2008, 26, 1187– 1192, DOI: 10.1038/nbt.1496[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1aisr3K&md5=f80228275d0e19e40e049ea715c11895Small-molecule inhibition of HIV-1 VifNathans, Robin; Cao, Hong; Sharova, Natalia; Ali, Akbar; Sharkey, Mark; Stranska, Ruzena; Stevenson, Mario; Rana, Tariq M.Nature Biotechnology (2008), 26 (10), 1187-1192CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)The HIV-1 protein Vif, essential for in vivo viral replication, targets the human DNA-editing enzyme, APOBEC3G (A3G), which inhibits replication of retroviruses and hepatitis B virus. As Vif has no known cellular homologs, it is an attractive, yet unrealized, target for antiviral intervention. Although zinc chelation inhibits Vif and enhances viral sensitivity to A3G, this effect is unrelated to the interaction of Vif with A3G. We identify a small mol., RN-18, that antagonizes Vif function and inhibits HIV-1 replication only in the presence of A3G. RN-18 increases cellular A3G levels in a Vif-dependent manner and increases A3G incorporation into virions without inhibiting general proteasome-mediated protein degrdn. RN-18 enhances Vif degrdn. only in the presence of A3G, reduces viral infectivity by increasing A3G incorporation into virions and enhances cytidine deamination of the viral genome. These results demonstrate that the HIV-1 Vif-A3G axis is a valid target for developing small mol.-based new therapies for HIV infection or for enhancing innate immunity against viruses.
- 40Ali, A.; Wang, J.; Nathans, R. S.; Cao, H.; Sharova, N.; Stevenson, M.; Rana, T. M. Synthesis and structure-activity relationship studies of HIV-1 virion infectivity factor (Vif) inhibitors that block viral replication. ChemMedChem 2012, 7, 1217– 1229, DOI: 10.1002/cmdc.201200079[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsVansro%253D&md5=63cee4d4793348b9c67967d0680e9f2eSynthesis and Structure-Activity Relationship Studies of HIV-1 Virion Infectivity Factor (Vif) Inhibitors that Block Viral ReplicationAli, Akbar; Wang, Jinhua; Nathans, Robin S.; Cao, Hong; Sharova, Natalia; Stevenson, Mario; Rana, Tariq M.ChemMedChem (2012), 7 (7), 1217-1229, S1217/1-S1217/7CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)The human immunodeficiency virus 1 (HIV-1) virion infectivity factor (Vif) protein, essential for in vivo viral replication, protects the virus from innate antiviral cellular factor apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC3G; A3G) and is an attractive target for the development of novel antiviral therapeutics. We have evaluated the structure-activity relationships of N-(2-methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide (RN-18), a small mol. recently identified as an inhibitor of Vif function that blocks viral replication only in nonpermissive cells expressing A3G, by inhibiting Vif-A3G interactions. Microwave-assisted cross-coupling reactions were developed to prep. a series of RN18 analogs with diverse linkages and substitutions on the Ph rings. A dual cell-based assay system was used to assess antiviral activity against wild-type HIV-1 in both nonpermissive (H9) and permissive (MT4) cells that also allowed evaluation of specificity. In general, variations of Ph substitutions were detrimental to antiviral potency and specificity, but isosteric replacements of amide and ether linkages were relatively well tolerated. These structure-activity relationship data define structural requirements for Vif-specific activity, identify new compds. with improved antiviral potency and specificity, and provide leads for further exploration to develop new antiviral therapeutics.
- 41Mohammed, I.; Parai, M. K.; Jiang, X.; Sharova, N.; Singh, G.; Stevenson, M.; Rana, T. M. SAR and lead optimization of an HIV-1 Vif-APOBEC3G axis inhibitor. ACS Med. Chem. Lett. 2012, 3, 465– 469, DOI: 10.1021/ml300037k[ACS Full Text], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmvV2gtbY%253D&md5=346201d67c71ec1e05d1a185e9c207efSAR and Lead Optimization of an HIV-1 Vif-APOBEC3G Axis InhibitorMohammed, Idrees; Parai, Maloy K.; Jiang, Xinpeng; Sharova, Natalia; Singh, Gatikrushna; Stevenson, Mario; Rana, Tariq M.ACS Medicinal Chemistry Letters (2012), 3 (6), 465-469CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We describe structure-activity relationship and optimization studies of RN-18 (I), an HIV-1 Vif-APOBEC3G axis inhibitor. Targeted modifications of RN-18 ring C, ring B, ring A, bridge A-B, and bridge B-C were performed to identify the crucial structural features, which generated new inhibitors with similar (4g and 4i) and improved (5, 8b, and 11) activities. Two potent water-sol. RN-18 analogs, 17 and 19, are also disclosed, and we describe the results of pharmacol. studies with compd. 19. The findings described here will be useful in the development of more potent Vif inhibitors and in the design of probes to identify the target protein of RN-18 and its analogs.
- 42Miller, J. H.; Presnyak, V.; Smith, H. C. The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3G. Retrovirology 2007, 4, 81, DOI: 10.1186/1742-4690-4-81[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1c%252FnvFansA%253D%253D&md5=7d29a637af09daa3373d5d3f25923e69The dimerization domain of HIV-1 viral infectivity factor Vif is required to block virion incorporation of APOBEC3GMiller James H; Presnyak Vlad; Smith Harold CRetrovirology (2007), 4 (), 81 ISSN:.BACKGROUND: The HIV-1 accessory protein known as viral infectivity factor or Vif binds to the host defence factor human APOBEC3G (hA3G) and prevents its assembly with viral particles and mediates its elimination through ubiquitination and degradation by the proteosomal pathway. In the absence of Vif, hA3G becomes incorporated within viral particles. During the post entry phase of infection, hA3G attenuates viral replication by binding to the viral RNA genome and deaminating deoxycytidines to form deoxyuridines within single stranded DNA regions of the replicated viral genome. Vif dimerization has been reported to be essential for viral infectivity but the mechanistic requirement for Vif multimerization is unknown. RESULTS: We demonstrate that a peptide antagonist of Vif dimerization fused to the cell transduction domain of HIV TAT suppresses live HIV-1 infectivity. We show rapid cellular uptake of the peptide and cytoplasmic distribution. Robust suppression of viral infectivity was dependent on the expression of Vif and hA3G. Disruption of Vif multimerization resulted in the production of virions with markedly increased hA3G content and reduced infectivity. CONCLUSION: The role of Vif multimerization in viral infectivity of nonpermissive cells has been validated with an antagonist of Vif dimerization. An important part of the mechanism for this antiretroviral effect is that blocking Vif dimerization enables hA3G incorporation within virions. We propose that Vif multimers are required to interact with hA3G to exclude it from viral particles during their assembly. Blocking Vif dimerization is an effective means of sustaining hA3G antiretroviral activity in HIV-1 infected cells. Vif dimerization is therefore a validated target for therapeutic HIV-1/AIDS drug development.
- 43Ribeiro, A. C.; Maia e Silva, A.; Santa-Marta, M.; Pombo, A.; Moniz-Pereira, J.; Goncalves, J.; Barahona, I. Functional analysis of Vif protein shows less restriction of human immunodeficiency virus type 2 by APOBEC3G. J. Virol. 2005, 79, 823– 833, DOI: 10.1128/JVI.79.2.823-833.2005[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlt12itw%253D%253D&md5=ba45b7b49540573139a94c549897368bFunctional analysis of Vif protein shows less restriction of human immunodeficiency virus type 2 by APOBEC3GRibeiro, Ana Clara; Maia e Silva, Alexandra; Santa-Marta, Mariana; Pombo, Ana; Moniz-Pereira, Jose; Goncalves, Joao; Barahona, IsabelJournal of Virology (2005), 79 (2), 823-833CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)Viral infectivity factor (Vif) is one of the human immunodeficiency virus (HIV) accessory proteins and is conserved in the primate lentivirus group. This protein is essential for viral replication in vivo and for productive infection of nonpermissive cells, such as peripheral blood mononuclear cells (PBMC). Vif counteracts an antiretroviral cellular factor in nonpermissive cells named CEM15/APOBEC3G. Although HIV type 1 (HIV-1) Vif protein (Vif1) can be functionally replaced by HIV-2 Vif protein (Vif2), its identity is very small. Most of the functional studies have been carried out with Vif1. Characterization of functional domains of Vif2 may elucidate its function, as well as differences between HIV-1 and HIV-2 infectivity. Our aim was to identify the permissivity of different cell lines for HIV-2 vif-minus viruses. By mutagenesis specific conserved motifs of HIV-2 Vif protein were analyzed, as well as in conserved motifs between Vif1 and Vif2 proteins. Vif2 mutants were examd. for their stability, expression, and cellular localization in order to characterize essential domains of Vif2 proteins. Viral replication in various target cells (PBMC and H9, A3.01, U38, and Jurkat cells) and infectivity in single cycle assays in the presence of APOBEC3G were also analyzed. Our results of viral replication show that only PBMC have a nonpermissive phenotype in the absence of Vif2. Moreover, the HIV-1 vif-minus nonpermissive cell line H9 does not show a similar phenotype for vif-neg. HIV-2. We also report a limited effect of APOBEC3G in a single-cycle infectivity assay, where only conserved domains between HIV-1 and HIV-2 Vif proteins influence viral infectivity. Taken together, these results allow us to speculate that viral inhibition by APOBEC3G is not the sole and most important determinant of antiviral activity against HIV-2.
- 44Mohammed, I.; Kummetha, I. R.; Singh, G.; Sharova, N.; Lichinchi, G.; Dang, J.; Stevenson, M.; Rana, T. M. 1,2,3-Triazoles as amide bioisosteres: discovery of a new class of potent HIV-1 Vif antagonists. J. Med. Chem. 2016, 59, 7677– 7682, DOI: 10.1021/acs.jmedchem.6b00247[ACS Full Text], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlSltb7F&md5=f75735900056b2f0975a13a8b6d7355a1,2,3-Triazoles as Amide Bioisosteres: Discovery of a New Class of Potent HIV-1 Vif AntagonistsMohammed, Idrees; Kummetha, Indrasena Reddy; Singh, Gatikrushna; Sharova, Natalia; Lichinchi, Gianluigi; Dang, Jason; Stevenson, Mario; Rana, Tariq M.Journal of Medicinal Chemistry (2016), 59 (16), 7677-7682CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)RN-18 based viral infectivity factor (Vif), Vif antagonists reduce viral infectivity by rescuing APOBEC3G (A3G) expression and enhancing A3G-dependent Vif degrdn. Replacement of amide functionality in RN-18 (IC50 = 6 μM) by isosteric heterocycles resulted in the discovery of a 1,2,3-trizole, 1d (IC50 = 1.2 μM). We identified several potent HIV-1 inhibitors from a 1d based library including 5ax (IC50 = 0.01 μM), 5bx (0.2 μM), 2ey (0.4 μM), 5ey (0.6 μM), and 6bx (0.2 μM).
- 45Rudin, C. M. Vismodegib. Clin. Cancer Res. 2012, 18, 3218– 3222, DOI: 10.1158/1078-0432.CCR-12-0568[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xos1Olt7Y%253D&md5=734079d44b61c0d8a28881dc9adda83aVismodegibRudin, Charles M.Clinical Cancer Research (2012), 18 (12), 3218-3222CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)A review. Vismodegib (GDC-0449), an orally bioavailable small-mol. inhibitor of Hedgehog signaling, was recently approved by the U.S. Food and Drug Administration for the treatment of basal cell carcinoma that is either metastatic or locally advanced in patients who are not candidates for surgical resection or radiation. Given the absence of previously defined effective drug therapy for this disease, approval was granted primarily on the basis of outcome of a nonrandomized parallel cohort phase II study of 99 patients with advanced basal cell carcinoma, with a primary endpoint of objective response rate. Response rates of 30.3% and 42.9% were obsd. in metastatic and locally advanced cohorts in this study, resp., assocd. with median progression-free survival in both cohorts of 9.5 mo. Ongoing clin. investigations include evaluation of the potential efficacy of vismodegib in a variety of diseases and in combination with other agents. The mechanism of action, preclin. and clin. data, and potential utility in other disease contexts are reviewed here. Clin Cancer Res; 18(12); 3218-22. ©2012 AACR.
- 46Cirrone, F.; Harris, C. S. Vismodegib and the hedgehog pathway: a new treatment for basal cell carcinoma. Clin. Ther. 2012, 34, 2039– 2050, DOI: 10.1016/j.clinthera.2012.08.011[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFSlsrjN&md5=62f4be4d8c749dd74f2a8e7d304447e4Vismodegib and the Hedgehog Pathway: A New Treatment for Basal Cell CarcinomaCirrone, Frank; Harris, Christy S.Clinical Therapeutics (2012), 34 (10), 2039-2050CODEN: CLTHDG; ISSN:0149-2918. (Elsevier)A review. Background: Vismodegib is an oral inhibitor of the Hedgehog pathway approved by the US Food and Drug Administration. It is the first systemic treatment for patients with locally advanced or metastatic basal cell carcinoma that is not amenable to surgery and radiation. This is the first drug to use the Hedgehog pathway to inhibit the proliferation of tumors and is also implicated in the development of other cancers such as medulloblastoma. Objective: The goal of this review was to summarize the development, pharmacol., efficacy, and safety of vismodegib. Methods: Relevant English-language literature was identified and then evaluated based on results from database searches of MEDLINE and EMBASE from 1975 to June 19, 2012. The terms searched included, but were not limited to, vismodegib, Erivedge, GDC-0449, basal cell carcinoma, and 2-chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]-4-(methylsulfonyl)benzamide. Addnl. literature was identified by assessing the ref. lists of previously identified articles and through abstrs. presented by the American Society of Clin. Oncol. Results: A total of 70 full text citations were identified although two national conference proceedings were then excluded. An addnl. 10 published abstrs. were also identified. A Phase II, nonrandomized, multicenter, international study demonstrated a 30.3% objective response rate in metastatic basal cell carcinoma and a 42.9% objective response rate in locally advanced basal cell carcinoma. The adverse effect profile for vismodegib is similar to other identified Hedgehog pathway inhibitors; muscle cramps (71.7%), alopecia (63.8%), and dysgeusia (55.1%) were the most common adverse effects seen in trials. A Phase II, randomized, placebo-controlled trial in Gorlin syndrome patients with basal cell carcinoma concluded that vismodegib was significantly better than placebo at reducing new basal cell carcinoma lesions (P < 0.001) and at decreasing the sum of the longest diam. of existing lesions (P = 0.003). Conclusions: For patients with unresectable basal cell carcinoma or where resection would be cosmetically disadvantageous, vismodegib is an effective therapy with good response rates. At this time, the data are too limited to det. overall survival. The Hedgehog pathway is a newly identified area in which mutations or dysregulation can occur, leading to the development and progression of tumors. Studies continue to look at other cancers with involvement of the Hedgehog pathway.
- 47Koelblinger, P.; Lang, R. New developments in the treatment of basal cell carcinoma: update on current and emerging treatment options with a focus on vismodegib. OncoTargets Ther. 2018, 11, 8327– 8340, DOI: 10.2147/OTT.S135650[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlKntrvK&md5=ba0dbaca1e5c8c8526b4cad32353450fNew developments in the treatment of basal cell carcinoma: update on current and emerging treatment options with a focus on vismodegibKoelblinger, Peter; Lang, RolandOncoTargets and Therapy (2018), 11 (), 8327-8340CODEN: OTNHAZ; ISSN:1178-6930. (Dove Medical Press Ltd.)Basal cell carcinoma (BCC) is the most common form of skin cancer worldwide. Although most BCCs can be treated by relatively simple surgical or nonsurgical methods, some patients with BCC may eventually develop advanced disease which can either be locally destructive or even include metastatic spread. The present review summarizes the current literature on the treatment of both early and advanced BCC with a focus on the hedgehog inhibitor vismodegib which has become an integral part of the management of patients with advanced BCC since its regulatory approval in 2012.
- 48Sharpe, H. J.; Pau, G.; Dijkgraaf, G. J.; Basset-Seguin, N.; Modrusan, Z.; Januario, T.; Tsui, V.; Durham, A. B.; Dlugosz, A. A.; Haverty, P. M.; Bourgon, R.; Tang, J. Y.; Sarin, K. Y.; Dirix, L.; Fisher, D. C.; Rudin, C. M.; Sofen, H.; Migden, M. R.; Yauch, R. L.; de Sauvage, F. J. Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma. Cancer Cell 2015, 27, 327– 341, DOI: 10.1016/j.ccell.2015.02.001[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXktFOgtrs%253D&md5=fe0aa6db03295a3250a3e7c3679e08f4Genomic Analysis of Smoothened Inhibitor Resistance in Basal Cell CarcinomaSharpe, Hayley J.; Pau, Gregoire; Dijkgraaf, Gerrit J.; Basset-Seguin, Nicole; Modrusan, Zora; Januario, Thomas; Tsui, Vickie; Durham, Alison B.; Dlugosz, Andrzej A.; Haverty, Peter M.; Bourgon, Richard; Tang, Jean Y.; Sarin, Kavita Y.; Dirix, Luc; Fisher, David C.; Rudin, Charles M.; Sofen, Howard; Migden, Michael R.; Yauch, Robert L.; de Sauvage, Frederic J.Cancer Cell (2015), 27 (3), 327-341CODEN: CCAECI; ISSN:1535-6108. (Elsevier Inc.)Smoothened (SMO) inhibitors are under clin. investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clin. benefit on vismodegib, but some develop resistance. Genomic anal. of tumor biopsies revealed that vismodegib resistance is assocd. with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy no. changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.
- 49Christodoulou, M. S.; Mori, M.; Pantano, R.; Alfonsi, R.; Infante, P.; Botta, M.; Damia, G.; Ricci, F.; Sotiropoulou, P. A.; Liekens, S.; Botta, B.; Passarella, D. Click reaction as a tool to combine pharmacophores: the case of vismodegib. ChemPlusChem 2015, 80, 938– 943, DOI: 10.1002/cplu.201402435[Crossref], [PubMed], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptFeqtLo%253D&md5=89723c9311c7de4d295eafcef5a3898dClick Reaction as a Tool to Combine Pharmacophores: The Case of VismodegibChristodoulou, Michael S.; Mori, Mattia; Pantano, Rebecca; Alfonsi, Romina; Infante, Paola; Botta, Maurizio; Damia, Giovanna; Ricci, Francesca; Sotiropoulou, Panagiota A.; Liekens, Sandra; Botta, Bruno; Passarella, DanieleChemPlusChem (2015), 80 (6), 938-943CODEN: CHEMM5; ISSN:2192-6506. (Wiley-VCH Verlag GmbH & Co. KGaA)The design and the prepn. of a small library of 1,4-diphenyl-1,2,3-triazole derivs. is reported, with the aim to obtain a new class of Hedgehog pathway inhibitors. The smoothened protein is part of the hedgehog signaling pathway that is inhibited by the lead compd. Vismodegib. Based on mol. modeling simulations, seven triazole derivs. of Vismodegib are synthesized and their biol. effect on different endothelial, cancer, and cancer stem cell lines is reported.
- 50Colombo, F.; Tintori, C.; Furlan, A.; Borrelli, S.; Christodoulou, M. S.; Dono, R.; Maina, F.; Botta, M.; Amat, M.; Bosch, J.; Passarella, D. ‘Click’ synthesis of a triazole-based inhibitor of Met functions in cancer cells. Bioorg. Med. Chem. Lett. 2012, 22, 4693– 4696, DOI: 10.1016/j.bmcl.2012.05.078[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xpt1Sgsbo%253D&md5=1fb77daf5aaff3028bca30587b940d63'Click' synthesis of a triazole-based inhibitor of Met functions in cancer cellsColombo, Francesco; Tintori, Cristina; Furlan, Alessandro; Borrelli, Stella; Christodoulou, Michael S.; Dono, Rosanna; Maina, Flavio; Botta, Maurizio; Amat, Mercedes; Bosch, Joan; Passarella, DanieleBioorganic & Medicinal Chemistry Letters (2012), 22 (14), 4693-4696CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The use of Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddn. permitted the synthesis of a new compd. (I) that is able to inhibit the HGF-induced scattering of MDCK (epithelial cells) and in vitro tumorigenesis of H1437 (non-small-cell lung cancer) and GTL-16 (human gastric carcinoma). In agreement with biochem. and biol. results, docking studies within the ATP binding site of Met suggested for the new synthesized compd. a binding mode similar to that of the active compd. Triflorcas previously reported.
- 51Furlan, A.; Roux, B.; Lamballe, F.; Conti, F.; Issaly, N.; Daian, F.; Guillemot, J. F.; Richelme, S.; Contensin, M.; Bosch, J.; Passarella, D.; Piccolo, O.; Dono, R.; Maina, F. Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures. PLoS One 2012, 7, e46738 DOI: 10.1371/journal.pone.0046738[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFCis7%252FI&md5=65339ecf250f39c9234abae6c8f95429Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signaturesFurlan, Alessandro; Roux, Benjamin; Lamballe, Fabienne; Conti, Filippo; Issaly, Nathalie; Daian, Fabrice; Guillemot, Jean-Francois; Richelme, Sylvie; Contensin, Magali; Bosch, Joan; Passarella, Daniele; Piccolo, Oreste; Dono, Rosanna; Maina, FlavioPLoS One (2012), 7 (10), e46738CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)The development of targeted mol. therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for mol. therapies. 2-Phenylimidazo[2,1-b]benzothiazole derivs. have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by "RTK swapping" by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addn. to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addn. to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivs. through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation.
- 52Arioli, F.; Borrelli, S.; Colombo, F.; Falchi, F.; Filippi, I.; Crespan, E.; Naldini, A.; Scalia, G.; Silvani, A.; Maga, G.; Carraro, F.; Botta, M.; Passarella, D. N-[2-methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine as a scaffold for the synthesis of inhibitors of Bcr-Abl. ChemMedChem 2011, 6e, 2009– 2018, DOI: 10.1002/cmdc.201100304
- 53Buchdunger, E.; O’Reilley, T.; Wood, J. Pharmacology of imatinib (STI571). Eur. J. Cancer 2002, 38 (Suppl. 5), S28– S36, DOI: 10.1016/S0959-8049(02)80600-1
- 54Hernandez-Boluda, J. C.; Cervantes, F. Imatinib mesylate (gleevec, glivec): a new therapy for chronic myeloid leukemia and other malignancies. Drugs Today (Barc) 2002, 38, 601– 613, DOI: 10.1358/dot.2002.38.9.696536[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s%252FntFequg%253D%253D&md5=3917aa8f7e8d02d13aaaffc683153272Imatinib mesylate (Gleevec, Glivec): a new therapy for chronic myeloid leukemia and other malignanciesHernandez-Boluda Juan Carlos; Cervantes FranciscoDrugs of today (Barcelona, Spain : 1998) (2002), 38 (9), 601-13 ISSN:1699-3993.Imatinib mesylate (STI571, Gleevec, Glivec, a selective inhibitor of the BCR-ABL tyrosine kinase causative of chronic myeloid leukemia (CML), represents the paradigm of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a targeted molecular therapy. Phase II clinical trials have shown marked therapeutic activity of imatinib in all evolutive phases of CML, but notably in the chronic phase, where it induces complete hematological responses in almost 100% of patients resistant or intolerant to interferon, with a major cytogenetic response rate of 60%, including 41% complete cytogenetic responses. The preliminary results of an ongoing phase III multicenter randomized study comparing imatinib with interferon plus cytarabine as first-line treatment for CML favor imatinib in terms of efficacy and safety. If confirmed with longer follow-up,these results would establish imatinib as the choice therapy for the majority of CML patients, with allogeneic transplantation being restricted as initial therapy only to younger patients with a family donor. Longer follow-up will answer some questions, such as those on long-term safety, durability of the responses, whether these will translate into a survival prolongation and the possibility of molecular responses. In addition, further information on the mechanisms involved in the primary and acquired resistance to imatinib is needed. Besides the Bcr-Abl protein, the drug is also active against other tyrosine kinases, such as Abl, the stem-cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this sense, it must be pointed out that imatinib has shown a remarkable activity in gastrointestinal stromal tumors.
- 55Moen, M. D.; McKeage, K.; Plosker, G. L.; Siddiqui, M. A. Imatinib: a review of its use in chronic myeloid leukaemia. Drugs 2007, 67, 299– 320, DOI: 10.2165/00003495-200767020-00010[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXksFOjsbk%253D&md5=b347c3ad7678bc9e17aaadbebd6cda53Imatinib: a review of its use in chronic myeloid leukaemiaMoen, Marit D.; McKeage, Kate; Plosker, Greg L.; Siddiqui, M. Asif A.; Berman, E.; Gambacorti-Passerini, C.; Goldman, J. H.; Hochhaus, A.; Larson, R. A.; Rosti, G.; Simonsson, B.Drugs (2007), 67 (2), 299-320CODEN: DRUGAY; ISSN:0012-6667. (Adis International Ltd.)A review. Imatinib (Gleevec, Glivec) is a synthetic tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (CML). It is specifically designed to inhibit the breakpoint cluster region (BCR)-Abelson (ABL) fusion protein that results from the chromosomal abnormality known as the Philadelphia chromosome. CML is characterized by this abnormality, which leads to abnormalities of the peripheral blood and bone marrow including an increase in the no. of granular leukocytes. Imatinib is approved in numerous countries worldwide for the treatment of newly diagnosed Philadelphia chromosome-pos. (Ph+) chronic-phase CML, Ph+ accelerated-phase or blast-crisis CML, and in patients with Ph+ chronic-phase CML who have failed to respond to interferon-α therapy. It is also indicated in pediatric patients with newly diagnosed Ph+ chronic-phase CML, in accelerated-phase or blast-crisis CML, or in chronic-phase CML after failure of interferon-α therapy or when the disease has recurred after hematopoietic stem cell transplantation (HSCT). Approved indications, however, may vary by country. Imatinib is effective and generally well tolerated in patients with Ph+ CML. In patients with newly diagnosed chronic-phase CML, imatinib was more effective than interferon-α plus cytarabine in preventing progression of the disease and in achieving haematol. and cytogenetic responses. Overall survival rates remain high after 5 years of follow-up, and historical comparisons with other treatments demonstrate improved overall survival with imatinib in the long term. Patients with accelerated-phase or blast-crisis CML, or those who have not responded to prior interferon-α therapy also benefit from imatinib treatment. Some patients become resistant or intolerant to imatinib therapy; management strategies to overcome these problems include dosage adjustment, other treatments, or combination therapy with imatinib and other agents. Allogeneic HSCT is currently the only potentially curative treatment, but it is assocd. with high rates of morbidity and mortality and is not suitable for all patients. The introduction of imatinib has had a marked impact on outcomes in patients with CML. It remains a valuable treatment for all stages of the disease, esp. initial treatment of newly diagnosed Ph+ chronic-phase CML, and is endorsed by European and US treatment guidelines as a first-line option. Pharmacol. Properties Imatinib inhibits BCR-ABL tyrosine kinase, which is expressed by CML cells with the Philadelphia chromosome abnormality. It also inhibits the receptor tyrosine kinases for platelet-derived growth factor and stem cell factor. Administration of imatinib to CML patients results in marked changes in bone marrow histopathol. and normalization of bone marrow vascularity in some patients. Primary or acquired resistance to imatinib is common in patients with advanced CML. There are several mechanisms of resistance and most involve reactivation of BCR-ABL signalling. Serial measurements of BCR-ABL transcript levels and ABL mutational screening can help identify the presence of BCR-ABL tyrosine kinase domain mutations and thereby emerging resistance. Following oral administration, imatinib is rapidly absorbed. The bioavailability of imatinib is 98%, and peak plasma concns. are reached after 2-4 h. Imatinib is metabolized by the liver and is primarily eliminated via the feces as unchanged parent drug and metabolites. Dosage adjustments are recommended in patients with severe hepatic dysfunction. Systemic exposure of imatinib may be altered when the drug is coadministered with various cytochrome P 450 inducers or inhibitors. Therapeutic Efficacy In a randomized, nonblind, multicenter phase III trial in patients with newly diagnosed Ph+ chronic-phase CML, imatinib significantly improved the estd. rates of survival without progression and survival without progression to accelerated-phase or blast-crisis CML compared with interferon-α plus cytarabine at median follow-ups of 19 and 30 mo. Haematol. and cytogenetic responses were also significantly greater in the imatinib group at both follow-ups. Rates of freedom from progression and haematol. and cytogenetic response remained high in imatinib recipients at a 60-mo follow-up of the phase III trial, although comparisons with interferon-α plus cytarabine recipients were not possible, as the majority of those randomized to interferon-α plus cytarabine had crossed over to the imatinib treatment arm. For the same reason, a between-treatment group comparison of overall survival in the phase III study was not possible. In an historical comparison between different trials, overall survival rates at 36 mo for imatinib recipients in the phase III trial were significantly higher than those for interferon-α plus cytarabine recipients in another study. Imatinib also produced high rates of haematol. and cytogenetic responses in phase II trials of Ph+ patients with accelerated-phase or blast-crisis CML, and in those who received second-line imatinib, with long-term follow-up (median 60 mo), after failure of interferon-α therapy. Cost-effectiveness analyses generally predict that imatinib is a costly, but generally cost-effective, treatment option; it is more effective and less costly than bone marrow transplantation. Tolerability Imatinib was generally well tolerated. Most imatinib recipients in the phase II and III studies experienced adverse events, usually of mild to moderate severity. The most common nonhaematol. adverse events in patients with chronic-phase CML were superficial edema, muscle cramps, diarrhea, nausea and musculo-skeletal pain. Similar tolerability profiles were seen in the phase II studies in patients with accelerated-phase or blast-crisis CML, and in those who had failed to respond to prior therapy with interferon-α. Grade 3 or 4 neutropenia, thrombocytopenia and anemia occurred in imatinib recipients in all phase II studies and in the phase III study, and appeared to be more severe in patients with advanced disease. In patients with chronic-phase CML in the phase III study, the incidences of grade 3 plus 4 neutropenia and thrombocytopenia were significantly lower in imatinib recipients than in those who received interferon-α plus cytarabine.
- 56Waller, C. F. Imatinib mesylate. Recent Results Cancer Res. 2010, 184, 3– 20, DOI: 10.1007/978-3-642-01222-8_1[Crossref], [PubMed], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlKgsLnM&md5=8a17d6a0511083508841a45d35a8de46Imatinib mesylateWaller, Cornelius F.Recent Results in Cancer Research (2010), 184 (Small Molecules in Oncology), 3-20CODEN: RRCRBU; ISSN:0080-0015. (Springer GmbH)A review. IMATINIB MESYLATE (Gleevec, Glivec [Novartis, Basel, Switzerland], formerly referred to as STI571 or CGP57148B) represents the paradigm of a new class of anticancer agents, the so-called small mols. They have a high selectivity against a specific mol. target known to be the cause for the establishment and maintenance of the malignant phenotype. Imatinib is a rationally designed oral signal transduction inhibitor that specifically targets several protein tyrosine kinases, Abl, Arg (Abl-related gene), the stem-cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGF-R), and their oncogenic forms, most notably Bcr-Abl. Imatinib has been shown to have remarkable clin. activity in patients with chronic myeloid leukemia (CML) and malignant gastrointestinal stroma tumors (GIST) leading to its approval for treatment of these diseases. Treatment with imatinib is generally well tolerated with a low incidence of severe side effects. The most common adverse events (AE) include mild to moderate edema, muscle cramps, diarrhea, nausea, skin rashes, and myelosuppression. Several mechanisms of resistance have been identified. Clonal evolution, amplification, or overexpression of Bcr-Abl as well as mutations in the catalytic domain, P-loop, and other mutations have been demonstrated to play a role in primary and secondary resistance to imatinib, resp. Improved understanding of the underlying mechanisms of resistance has led to the development of new second-generation tyrosine kinase inhibitors.
- 57Iqbal, N.; Iqbal, N. Imatinib: a breakthrough of targeted therapy in cancer. Chemother. Res. Pract. 2014, 2014, 357027, DOI: 10.1155/2014/357027[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfmsF2ntQ%253D%253D&md5=a11c9083960b6e9fb322a5671fbbc9d1Imatinib: a breakthrough of targeted therapy in cancerIqbal Nida; Iqbal NaveedChemotherapy research and practice (2014), 2014 (), 357027 ISSN:2090-2107.Deregulated protein tyrosine kinase activity is central to the pathogenesis of human cancers. Targeted therapy in the form of selective tyrosine kinase inhibitors (TKIs) has transformed the approach to management of various cancers and represents a therapeutic breakthrough. Imatinib was one of the first cancer therapies to show the potential for such targeted action. Imatinib, an oral targeted therapy, inhibits tyrosine kinases specifically BCR-ABL, c-KIT, and PDGFRA. Apart from its remarkable success in CML and GIST, Imatinib benefits various other tumors caused by Imatinib-specific abnormalities of PDGFR and c-KIT. Imatinib has also been proven to be effective in steroid-refractory chronic graft-versus-host disease because of its anti-PDGFR action. This paper is a comprehensive review of the role of Imatinib in oncology.
- 58Schenone, S.; Bruno, O.; Radi, M.; Botta, M. New insights into small-molecule inhibitors of Bcr-Abl. Med. Res. Rev. 2011, 31, 1– 41, DOI: 10.1002/med.20175[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3M%252Fis12gsA%253D%253D&md5=31f5f6ac39058db5fc2b49e80f0124deNew insights into small-molecule inhibitors of Bcr-AblSchenone S; Bruno O; Radi M; Botta MMedicinal research reviews (2011), 31 (1), 1-41 ISSN:.Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a defined genetic abnormality, the Bcr-Abl fusion gene on the Philadelphia chromosome that expresses the constitutively activated tyrosine kinase (TK) Bcr-Abl. This enzyme leads to the malignant transformation of primitive hematopoietic cells and to the consequent disease. The central role of Bcr-Abl in the pathogenesis of CML culminated in the discovery of imatinib (an ATP-competitive inhibitor), which is currently the frontline therapy for CML. Unfortunately, the initial enthusiasm generated by its high response rate has been dampened by the development of resistance, especially in the advanced phases of CML. To overcome imatinib resistance, several second-generation ATP-competitive inhibitors endowed with increased potency against imatinib-resistant mutants have been developed: the dual Src/Abl inhibitor dasatinib and the Abl inhibitor nilotinib have been recently approved by US-FDA for the treatment of imatinib-resistant CML, and many other compounds are currently in clinical trial. Although second-generation TK inhibitors have shown to be clinically effective against most of the imatinib-resistant mutants, to date poor results have been obtained in the treatment of the Bcr-Abl T315I mutant. In this review we will report the most interesting second-generation Abl and dual Src/Abl inhibitors recently entered in clinical trial, but also the new ATP-competitive and uncompetitive inhibitors published in the last few years, focusing on their chemical structure, mechanism of action, and structure-activity relationship.
- 59Leggio, G. M.; Bucolo, C.; Platania, C. B.; Salomone, S.; Drago, F. Current drug treatments targeting dopamine D3 receptor. Pharmacol. Ther. 2016, 165, 164– 177, DOI: 10.1016/j.pharmthera.2016.06.007[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVGisbfF&md5=e29dffe5b17b48f68d33ec838ece35dcCurrent drug treatments targeting dopamine D3 receptorLeggio, Gian Marco; Bucolo, Claudio; Platania, Chiara Bianca Maria; Salomone, Salvatore; Drago, FilippoPharmacology & Therapeutics (2016), 165 (), 164-177CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)Dopamine receptors (DR) have been extensively studied, but only in recent years they became object of investigation to elucidate the specific role of different subtypes (D1R, D2R, D3R, D4R, D5R) in neural transmission and circuitry. D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D2R and D4R) differ in signal transduction, binding profile, localization in the central nervous system and physiol. effects. D3R is involved in a no. of pathol. conditions, including schizophrenia, Parkinson's disease, addiction, anxiety, depression and glaucoma. Development of selective D3R ligands has been so far challenging, due to the high sequence identity and homol. shared by D2R and D3R. As a consequence, despite a rational design of selective DR ligands has been carried out, none of currently available medicines selectively target a given D2-like receptor subtype. The availability of the D3R ligand [11C]-(+)-PHNO for positron emission tomog. studies in animal models as well as in humans, allows researchers to est. the expression of D3R in vivo; displacement of [11C]-(+)-PHNO binding by concurrent drug treatments is used to est. the in vivo occupancy of D3R. Here we provide an overview of studies indicating D3R as a target for pharmacol. therapy, and a review of market approved drugs endowed with significant affinity at D3R that are used to treat disorders where D3R plays a relevant role.
- 60Joyce, J. N. Dopamine D3 receptor as a therapeutic target for antipsychotic and antiparkinsonian drugs. Pharmacol. Ther. 2001, 90, 231– 259, DOI: 10.1016/S0163-7258(01)00139-5[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXntV2hur8%253D&md5=70af1ac4de6b531b5b3b13f0fe179d0fDopamine D3 receptor as a therapeutic target for antipsychotic and antiparkinsonian drugsJoyce, J. N.Pharmacology & Therapeutics (2001), 90 (2-3), 231-259CODEN: PHTHDT; ISSN:0163-7258. (Elsevier Science Inc.)A review. The cloning of the gene for the D3 receptor and subsequent identification of its distribution in brain and pharmacol. allowed for serious consideration of the possibility that it might be a target for drugs used to treat schizophrenia and Parkinson's disease (PD). That is because it is highly expressed in limbic regions of the brain, exhibits low expression in motor divisions, and has pharmacol. similarity to the D2 receptor. Thus, antipsychotics that were presumed to block D2 receptors also had high affinity for the D3 receptor. Dopamine agonists used to treat the clin. symptoms of PD also have high affinity for the D3 receptor, and two D3 receptor-preferring agonists were effective for treatment of PD. Many compds. achieving high potency and selectivity are now available, but few have reached clin. testing. Recent findings with respect to the anatomy of this receptor in human brain, altered expression in schizophrenia and PD, and biol. models to study its function support the proposal that it is a target for development of drugs to alleviate symptoms in neuropsychiatric and neurol. disorders. Because of distinct aspects of regulation of the D3 receptor, it represents a unique target for therapeutic intervention in schizophrenia without high potential for unintended side effects such as tardive dyskinesia. It may also be that D3 receptor agonists can provide neuroprotective effects in PD and can modify clin. symptoms that D2 receptor-preferring agonists cannot provide.
- 61Maramai, S.; Gemma, S.; Brogi, S.; Campiani, G.; Butini, S.; Stark, H.; Brindisi, M. Dopamine D3 receptor antagonists as potential therapeutics for the treatment of neurological diseases. Front. Neurosci. 2016, 10, 451, DOI: 10.3389/fnins.2016.00451[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srktFCktA%253D%253D&md5=03b1e02b49ea48ab9331f5c9d38dfaf1Dopamine D3 Receptor Antagonists as Potential Therapeutics for the Treatment of Neurological DiseasesMaramai Samuele; Gemma Sandra; Brogi Simone; Campiani Giuseppe; Butini Stefania; Brindisi Margherita; Stark HolgerFrontiers in neuroscience (2016), 10 (), 451 ISSN:1662-4548.D3 receptors represent a major focus of current drug design and development of therapeutics for dopamine-related pathological states. Their close homology with the D2 receptor subtype makes the development of D3 selective antagonists a challenging task. In this review, we explore the relevance and therapeutic utility of D3 antagonists or partial agonists endowed with multireceptor affinity profile in the field of central nervous system disorders such as schizophrenia and drug abuse. In fact, the peculiar distribution and low brain abundance of D3 receptors make them a valuable target for the development of drugs devoid of motor side effects classically elicited by D2 antagonists. Recent research efforts were devoted to the conception of chemical templates possibly endowed with a multi-target profile, especially with regards to other G-protein-coupled receptors (GPCRs). A comprehensive overview of the recent literature in the field is herein provided. In particular, the evolution of the chemical templates has been tracked, according to the growing advancements in both the structural information and the refinement of the key pharmacophoric elements. The receptor/multireceptor affinity and functional profiles for the examined compounds have been covered, together with their most significant pharmacological applications.
- 62Newman, A. H.; Grundt, P.; Cyriac, G.; Deschamps, J. R.; Taylor, M.; Kumar, R.; Ho, D.; Luedtke, R. R. N-(4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with functionalized linking chains as high affinity and enantioselective D3 receptor antagonists. J. Med. Chem. 2009, 52, 2559– 2570, DOI: 10.1021/jm900095y[ACS Full Text], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktFGrt7s%253D&md5=665731381e379cec45ef058cd6c45d0eN-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor AntagonistsNewman, Amy Hauck; Grundt, Peter; Cyriac, George; Deschamps, Jeffrey R.; Taylor, Michelle; Kumar, Rakesh; Ho, David; Luedtke, Robert R.Journal of Medicinal Chemistry (2009), 52 (8), 2559-2570CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl- and 2-OCH3-phenylpiperazine class of compds. with the goal to improve D3 receptor affinity and selectivity. This extension of structure-activity relationships (SAR) has resulted in the identification of the first enantioselective D3 antagonists (R- and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2, and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compds. reported to date that show high affinity (Ki = 1 nM) for D3 and ∼400-fold selectivity over the D2 receptor subtype. Several of these analogs showed exquisite selectivity for D3 receptors over >60 other receptors, further underscoring their value as in vivo research tools. These lead compds. also have appropriate phys. characteristics for in vivo exploration and therefore will be useful in detg. how intrinsic activity at D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric disorders.
- 63Boateng, C. A.; Bakare, O. M.; Zhan, J.; Banala, A. K.; Burzynski, C.; Pommier, E.; Keck, T. M.; Donthamsetti, P.; Javitch, J. A.; Rais, R.; Slusher, B. S.; Xi, Z. X.; Newman, A. H. High affinity dopamine D3 Receptor (D3R)-selective antagonists attenuate heroin self-administration in wild-type but not D3R knockout mice. J. Med. Chem. 2015, 58, 6195– 6213, DOI: 10.1021/acs.jmedchem.5b00776[ACS Full Text], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1alur%252FK&md5=1724065cac8ac51295cf4660a20ed734High Affinity Dopamine D3 Receptor (D3R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D3R Knockout MiceBoateng, Comfort A.; Bakare, Oluyomi M.; Zhan, Jia; Banala, Ashwini K.; Burzynski, Caitlin; Pommier, Elie; Keck, Thomas M.; Donthamsetti, Prashant; Javitch, Jonathan A.; Rais, Rana; Slusher, Barbara S.; Xi, Zheng-Xiong; Newman, Amy HauckJournal of Medicinal Chemistry (2015), 58 (15), 6195-6213CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The dopamine D3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models of drug abuse, esp. in models of relapse. Nevertheless, poor bioavailability, metabolic instability, and/or predicted toxicity have impeded success in translating these drug candidates to clin. use. Herein, the authors report a series of D3R-selective 4-phenylpiperazines with improved metabolic stability. A subset of these compds. was evaluated for D3R functional efficacy and off-target binding at selected 5-HT receptor subtypes, where significant overlap in SAR with D3R has been obsd. Several high affinity D3R antagonists, including compds. I (Ki = 0.12 nM) and II (Ki = 0.35 nM), showed improved metabolic stability compared to the parent compd., PG648. Notably, I and the classic D3R antagonist SB277011A were effective in reducing self-administration of heroin in wild-type but not D3R knockout mice.
- 64Heidbreder, C. A.; Newman, A. H. Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders. Ann. N. Y. Acad. Sci. 2010, 1187, 4– 34, DOI: 10.1111/j.1749-6632.2009.05149.x[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXks1Snurc%253D&md5=48ded12d27f36b8d77717b118ccfa869Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disordersHeidbreder, Christian A.; Newman, Amy H.Annals of the New York Academy of Sciences (2010), 1187 (Addiction Reviews 2), 4-34CODEN: ANYAA9; ISSN:0077-8923. (Wiley-Blackwell)A review. Repeated exposure to drugs of abuse produces long-term mol. and neurochem. changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing no. of new mol. and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D3 receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D3 receptor antagonists. Growing preclin. evidence indicates that these compds. may actually regulate the motivation to self-administer drugs and disrupt drug-assocd. cue-induced craving. This report will be divided into three parts. First, preclin. evidence in support of the efficacy of selective DA D3 receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D2/D3 receptor antagonists will not be discussed here because most of these compds. have low selectivity at the D3 vs. D2 receptor, and their efficacy profile is related primarily to functional antagonism at D2 receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chem. for the identification and optimization of selective DA D3 receptor antagonists and partial agonists will be analyzed. Third, translational research from preclin. efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed.
- 65Banala, A. K.; Levy, B. A.; Khatri, S. S.; Furman, C. A.; Roof, R. A.; Mishra, Y.; Griffin, S. A.; Sibley, D. R.; Luedtke, R. R.; Newman, A. H. N-(3-fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as selective dopamine D3 receptor ligands: critical role of the carboxamide linker for D3 receptor selectivity. J. Med. Chem. 2011, 54, 3581– 3594, DOI: 10.1021/jm200288r[ACS Full Text], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsVyhsbw%253D&md5=4fecff363e5628b365e7aeba6a824f9dN-(3-Fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as Selective Dopamine D3 Receptor Ligands: Critical Role of the Carboxamide Linker for D3 Receptor SelectivityBanala, Ashwini K.; Levy, Benjamin A.; Khatri, Sameer S.; Furman, Cheryse A.; Roof, Rebecca A.; Mishra, Yogesh; Griffin, Suzy A.; Sibley, David R.; Luedtke, Robert R.; Newman, Amy HauckJournal of Medicinal Chemistry (2011), 54 (10), 3581-3594CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)N-(3-Fluoro-4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)arylcarboxamides were prepd. and evaluated for binding and function at dopamine D3 receptors (D3Rs) and dopamine D2 receptors (D2Rs). In this series, we discovered some of the most D3R selective compds. reported to date (e.g., I, >1000-fold D3R-selective over D2R). In addn., chimeric receptor studies further identified the second extracellular (E2) loop as an important contributor to D3R binding selectivity. Further, compds. lacking the carbonyl group in the amide linker were synthesized, and while these amine-linked analogs bound with similar affinities to the amides at D2R, this modification dramatically reduced binding affinities at D3R by >100-fold, resulting in compds. with significantly reduced D3R selectivity. This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compds. and further reveals a point of sepn. between structure-activity relationships at D3R and D2R.
- 66Keck, T. M.; Banala, A. K.; Slack, R. D.; Burzynski, C.; Bonifazi, A.; Okunola-Bakare, O. M.; Moore, M.; Deschamps, J. R.; Rais, R.; Slusher, B. S.; Newman, A. H. Using click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligands. Bioorg. Med. Chem. 2015, 23, 4000– 4012, DOI: 10.1016/j.bmc.2015.01.017[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1Oju7w%253D&md5=d35aea3134fe53f9d5bea86519ce6e8fUsing click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligandsKeck, Thomas M.; Banala, Ashwini K.; Slack, Rachel D.; Burzynski, Caitlin; Bonifazi, Alessandro; Okunola-Bakare, Oluyomi M.; Moore, Martin; Deschamps, Jeffrey R.; Rais, Rana; Slusher, Barbara S.; Hauck Newman, AmyBioorganic & Medicinal Chemistry (2015), 23 (14), 4000-4012CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)The dopamine D3 receptor (D3R) is a target of pharmacotherapeutic interest in a variety of neurol. disorders including schizophrenia, Parkinson's disease, restless leg syndrome, and drug addiction. A common mol. template used in the development of D3R-selective antagonists and partial agonists incorporates a butylamide linker between two pharmacophores, a phenylpiperazine moiety and an extended aryl ring system. The series of compds. described herein incorporates a change to that chem. template, replacing the amide functional group in the linker chain with a 1,2,3-triazole group. Although the amide linker in the 4-phenylpiperazine class of D3R ligands has been previously deemed crit. for high D3R affinity and selectivity, the 1,2,3-triazole moiety serves as a suitable bioisosteric replacement and maintains desired D3R-binding functionality of the compds. Addnl., using mouse liver microsomes to evaluate CYP450-mediated phase I metab., the authors detd. that novel 1,2,3-triazole-contg. compds. modestly improves metabolic stability compared to amide-contg. analogs. The 1,2,3-triazole moiety allows for the modular attachment of chem. subunit libraries using copper-catalyzed azide-alkyne cycloaddn. click chem., increasing the range of chem. entities that can be designed, synthesized, and developed toward D3R-selective therapeutic agents.
- 67Appendino, G.; Bacchiega, S.; Minassi, A.; Cascio, M. G.; De Petrocellis, L.; Di Marzo, V. The 1,2,3-triazole ring as a peptido- and olefinomimetic element: discovery of click vanilloids and cannabinoids. Angew. Chem., Int. Ed. 2007, 46, 9312– 9315, DOI: 10.1002/anie.200703590[Crossref], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhslWksg%253D%253D&md5=7b74f7fce4f8462cc61822eb4d52bb83The 1,2,3-triazole ring as a peptido- and olefinomimetic element: discovery of click vanilloids and cannabinoidsAppendino, Giovanni; Bacchiega, Sara; Minassi, Alberto; Cascio, Maria Grazia; De Petrocellis, Luciano; Di Marzo, VincenzoAngewandte Chemie, International Edition (2007), 46 (48), 9312-9315CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Fooling nature: The replacement of amide and alkene groups in a biol. setting with the 1,2,3-triazole group led to the discovery of compds. with a unique vanilloid/cannabinoid mixed profile. For example, the natural amides (see picture, above) and their triazole mimics (below) exhibit similar agonistic (X = H) or antagonistic (X = I) activity towards the TRPV1 receptor; however, only the triazole derivs. also show cannabinomimetic activity.
- 68Mugnaini, C.; Nocerino, S.; Pedani, V.; Pasquini, S.; Tafi, A.; De Chiaro, M.; Bellucci, L.; Valoti, M.; Guida, F.; Luongo, L.; Dragoni, S.; Ligresti, A.; Rosenberg, A.; Bolognini, D.; Cascio, M. G.; Pertwee, R. G.; Moaddel, R.; Maione, S.; Di Marzo, V.; Corelli, F. Investigations on the 4-quinolone-3-carboxylic acid motif part 5: modulation of the physicochemical profile of a set of potent and selective cannabinoid-2 receptor ligands through a bioisosteric approach. ChemMedChem 2012, 7, 920– 934, DOI: 10.1002/cmdc.201100573[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtFOhtbo%253D&md5=4ac67390a8af749cd21afd9ef894099fInvestigations on the 4-Quinolone-3-Carboxylic Acid Motif Part 5: Modulation of the Physicochemical Profile of a Set of Potent and Selective Cannabinoid-2 Receptor Ligands through a Bioisosteric ApproachMugnaini, Claudia; Nocerino, Stefania; Pedani, Valentina; Pasquini, Serena; Tafi, Andrea; De Chiaro, Maria; Bellucci, Luca; Valoti, Massimo; Guida, Francesca; Luongo, Livio; Dragoni, Stefania; Ligresti, Alessia; Rosenberg, Avraham; Bolognini, Daniele; Cascio, Maria Grazia; Pertwee, Roger G.; Moaddel, Ruin; Maione, Sabatino; Di Marzo, Vincenzo; Corelli, FedericoChemMedChem (2012), 7 (5), 920-934CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Three heterocyclic systems were selected as potential bioisosteres of the amide linker for a series of 1,6-disubstituted-4-quinolone-3-carboxamides, which are potent and selective CB2 ligands that exhibit poor water soly., with the aim of improving their physicochem. profile and also of clarifying properties of importance for amide bond mimicry. Among the newly synthesized compds., a 1,2,3-triazole deriv. (1-(adamantan-1-yl)-4-[6-(furan-2-yl)-1,4-dihydro-4-oxo-1-pentylquinolin-3-yl]-1H-1,2,3-triazole) emerged as the most promising in terms of both physicochem. and pharmacodynamic properties. When assayed in vitro, this deriv. exhibited inverse agonist activity, whereas, in the formalin test in mice, it produced analgesic effects antagonized by a well-established inverse agonist. Metabolic studies allowed the identification of a side chain hydroxylated deriv. as its only metabolite, which, in its racemic form, still showed appreciable CB2 selectivity, but was 150-fold less potent than the parent compd.
- 69Cabral, G. A.; Griffin-Thomas, L. Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev. Mol. Med. 2009, 11, e3, DOI: 10.1017/S1462399409000957
- 70Dhopeshwarkar, A.; Mackie, K. CB2 Cannabinoid receptors as a therapeutic target-what does the future hold?. Mol. Pharmacol. 2014, 86, 430– 437, DOI: 10.1124/mol.114.094649[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs12iu7nN&md5=76d3335b4ef5194f805f67619466739bCB2 cannabinoid receptors as a therapeutic target - what does the future hold?Dhopeshwarkar, Amey; Mackie, KenMolecular Pharmacology (2014), 86 (4), 430-437, 8 pp.CODEN: MOPMA3; ISSN:1521-0111. (American Society for Pharmacology and Experimental Therapeutics)A review. The past decades have seen an exponential rise in our understanding of the endocannabinoid system, comprising CB1 and CB2 cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that synthesize and degrade endocannabinoids. The primary focus of this review is the CB2 receptor. CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential for treating various pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor-based therapies. With the appreciation that CB2-selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research from both a mechanistic as well as a therapeutic perspective. In this review, we summarize our present knowledge of CB2 receptor signaling, localization, and regulation. We discuss the availability of genetic tools (and their limitations) to study CB2 receptors and also provide an update on preclin. data on CB2 agonists in pain models. Finally, we suggest possible reasons for the failure of CB2 ligands in clin. pain trials and offer possible ways to move the field forward in a way that can help reconcile the inconsistencies between preclin. and clin. data.
- 71Turcotte, C.; Blanchet, M. R.; Laviolette, M.; Flamand, N. The CB2 receptor and its role as a regulator of inflammation. Cell. Mol. Life Sci. 2016, 73, 4449– 4470, DOI: 10.1007/s00018-016-2300-4[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFCrtLrN&md5=572eaca44428863b1c69dde0bca87662The CB2 receptor and its role as a regulator of inflammationTurcotte, Caroline; Blanchet, Marie-Renee; Laviolette, Michel; Flamand, NicolasCellular and Molecular Life Sciences (2016), 73 (23), 4449-4470CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Basel)The CB2 receptor is the peripheral receptor for cannabinoids. It is mainly expressed in immune tissues, highlighting the possibility that the endocannabinoid system has an immunomodulatory role. In this respect, the CB2 receptor was shown to modulate immune cell functions, both in cellulo and in animal models of inflammatory diseases. In this regard, numerous studies have reported that mice lacking the CB2 receptor have an exacerbated inflammatory phenotype. This suggests that therapeutic strategies aiming at modulating CB2 signaling could be promising for the treatment of various inflammatory conditions. Herein, we review the pharmacol. of the CB2 receptor, its expression pattern, and the signaling pathways induced by its activation. We next examine the regulation of immune cell functions by the CB2 receptor and the evidence obtained from primary human cells, immortalized cell lines, and animal models of inflammation. Finally, we discuss the possible therapies targeting the CB2 receptor and the questions that remain to be addressed to det. whether this receptor could be a potential target to treat inflammatory disease.
- 72Koufaki, M.; Detsi, A.; Theodorou, E.; Kiziridi, C.; Calogeropoulou, T.; Vassilopoulos, A.; Kourounakis, A. P.; Rekka, E.; Kourounakis, P. N.; Gaitanaki, C.; Papazafiri, P. Synthesis of chroman analogues of lipoic acid and evaluation of their activity against reperfusion arrhythmias. Bioorg. Med. Chem. 2004, 12, 4835– 4841, DOI: 10.1016/j.bmc.2004.07.012[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXntFSntbk%253D&md5=4e935fc643ff40bd4aa134010e1018f8Synthesis of chroman analogues of lipoic acid and evaluation of their activity against reperfusion arrhythmiasKoufaki, Maria; Detsi, Anastasia; Theodorou, Elissavet; Kiziridi, Christina; Calogeropoulou, Theodora; Vassilopoulos, Athanasios; Kourounakis, Angeliki P.; Rekka, Eleni; Kourounakis, Panos N.; Gaitanaki, Catherine; Papazafiri, PanagiotaBioorganic & Medicinal Chemistry (2004), 12 (18), 4835-4841CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)Novel hybrids of lipoic acid and trolox connected through triamine spacers as well as analogs in which the lipoic acid was attached at different positions of the chroman moiety of vitamin E through an amide bond, were synthesized and exhibited strong inhibition of the microsomal lipid peroxidn. Moreover, the new mols., e.g., I, at 1 μM concn., reduced reperfusion arrhythmias and MDA content on isolated rat heart prepns., with the 2- and 5-substituted chromans possessing the better cardioprotective activity.
- 73Koufaki, M.; Kiziridi, C.; Alexi, X.; Alexis, M. N. Design and synthesis of novel neuroprotective 1,2-dithiolane/chroman hybrids. Bioorg. Med. Chem. 2009, 17, 6432– 6441, DOI: 10.1016/j.bmc.2009.07.010[Crossref], [PubMed], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVenur3J&md5=798070233784afcaf51b380ff14b00b9Design and synthesis of novel neuroprotective 1,2-dithiolane/chroman hybridsKoufaki, Maria; Kiziridi, Christina; Alexi, Xanthippi; Alexis, Michael N.Bioorganic & Medicinal Chemistry (2009), 17 (17), 6432-6441CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Novel 1,2-dithiolane/chroman hybrids bearing heterocyclic rings such as 1,2,4- and 1,3,4-oxadiazole, 1,2,3-triazole and tetrazole were designed and synthesized. The neuroprotective activity of the new analogs was tested against oxidative stress-induced cell death of glutamate-challenged HT22 hippocampal neurons. Our results show that bioisosteric replacement of amide group in 2-position of the chroman moiety, by 1,3,4-oxadiazole did not affect activity. However, analog 5 (I) bearing the 1,2,4-oxadiazole moiety showed improved neuroprotective activity. The presence of nitrogen heterocycles strongly influences the neuroprotective activity of 5-substituted chroman derivs., depending on the nature of heterocycle. Replacement of the amide group of the first generation analogs by 1,2,4-oxadiazole or 1,2,3-triazole resulted in significant improvement of the activity against glutamate induced oxidative stress.
- 74Koufaki, M.; Calogeropoulou, T.; Detsi, A.; Roditis, A.; Kourounakis, A. P.; Papazafiri, P.; Tsiakitzis, K.; Gaitanaki, C.; Beis, I.; Kourounakis, P. N. Novel potent inhibitors of lipid peroxidation with protective effects against reperfusion arrhythmias. J. Med. Chem. 2001, 44, 4300– 4303, DOI: 10.1021/jm010962w[ACS Full Text], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnvVOjs78%253D&md5=281895d241c853441bf368a5291e06beNovel Potent Inhibitors of Lipid Peroxidation with Protective Effects against Reperfusion ArrhythmiasKoufaki, Maria; Calogeropoulou, Theodora; Detsi, Anastasia; Roditis, Aristidis; Kourounakis, Angeliki P.; Papazafiri, Panagiota; Tsiakitzis, Karyofyllis; Gaitanaki, Catherine; Beis, Isidoros; Kourounakis, Panos N.Journal of Medicinal Chemistry (2001), 44 (24), 4300-4303CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of new compds. that contain lipoic acid and trolox connected through spacers were synthesized and examd. for their antioxidant activity and their protective effects against reperfusion arrhythmias in isolated heart prepns. All compds. tested are strong inhibitors of lipid peroxidn. in rat liver microsomal membranes induced by ferrous ions and ascorbate. N-(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carbonyl)-N'-(1,2-dithiolane-3-pentanoyl)-1,2-phenylenediamine (I) exhibits anti-lipid peroxidn. activity at the nanomolar range. N-(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carbonyl)-N'-(1,2-dithiolane-3-pentanoyl)ethylenediamine (II) and I totally suppressed reperfusion arrhythmias.
- 75Rosini, M.; Andrisano, V.; Bartolini, M.; Bolognesi, M. L.; Hrelia, P.; Minarini, A.; Tarozzi, A.; Melchiorre, C. Rational approach to discover multipotent anti-Alzheimer drugs. J. Med. Chem. 2005, 48, 360– 363, DOI: 10.1021/jm049112h[ACS Full Text], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjslSk&md5=e632c934e744d35d5acf7047827fc91fRational Approach To Discover Multipotent Anti-Alzheimer DrugsRosini, Michela; Andrisano, Vincenza; Bartolini, Manuela; Bolognesi, Maria L.; Hrelia, Patrizia; Minarini, Anna; Tarozzi, Andrea; Melchiorre, CarloJournal of Medicinal Chemistry (2005), 48 (2), 360-363CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The coupling of two different pharmacophores, each endowed with different biol. properties, afforded the hybrid compd. lipocrine (7), whose biol. profile was markedly improved relative to those of prototypes tacrine and lipoic acid. Lipocrine is the first compd. that inhibits the catalytic activity of AChE and AChE-induced amyloid-β aggregation and protects against reactive oxygen species. Thus, it emerged as a valuable pharmacol. tool to investigate Alzheimer's disease and as a promising lead compd. for new anti-Alzheimer drugs.
- 76Maczurek, A.; Shanmugam, K.; Munch, G. Inflammation and the redox-sensitive AGE-RAGE pathway as a therapeutic target in Alzheimer’s disease. Ann. N. Y. Acad. Sci. 2008, 1126, 147– 151, DOI: 10.1196/annals.1433.026[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmtFygu74%253D&md5=a663abce366feec4856af9ab830c9bc8Inflammation and the redox-sensitive AGE-RAGE pathway as a therapeutic target in Alzheimer's diseaseMaczurek, Annette; Shanmugam, Kirubakaran; Muench, GeraldAnnals of the New York Academy of Sciences (2008), 1126 (Maillard Reaction), 147-151CODEN: ANYAA9; ISSN:0077-8923. (Blackwell Publishing, Inc.)A review. Alzheimer's disease (AD) is the most common cause of dementia. Neuritic amyloid plaques and concomitant chronic inflammation are prominent pathol. features of AD. β-Amyloid peptide (Aβ), the major component of plaques, and advanced glycation end products (AGEs), post-translational protein modifications, are key activators of plaque-assocd. inflammation. Aβ, AGEs, S100b, and amphoterin bind to the receptor for AGEs (RAGE), which transmits the signal from RAGE via redox-sensitive pathways to nuclear factor kappa-B (NF-κB)-regulated cytokines. RAGE-mediated inflammation caused by glial cells and subsequent changes in neuronal glucose metab. are likely to be important contributors to neurodegeneration in AD. As long as the neuronal damage is reversible, drugs interfering with the Aβ and AGE-RAGE pathways might be interesting novel therapeutics for the treatment of AD.
- 77Harnett, J. J.; Auguet, M.; Viossat, I.; Dolo, C.; Bigg, D.; Chabrier, P. E. Novel lipoic acid analogues that inhibit nitric oxide synthase. Bioorg. Med. Chem. Lett. 2002, 12, 1439– 1442, DOI: 10.1016/S0960-894X(02)00216-0[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xjsl2lt7o%253D&md5=d85be5192fe6216a7159d3610636ab0aNovel lipoic acid analogues that inhibit nitric oxide synthaseHarnett, Jeremiah J.; Auguet, Michel; Viossat, Isabelle; Dolo, Christine; Bigg, Dennis; Chabrier, Pierre-E.Bioorganic & Medicinal Chemistry Letters (2002), 12 (11), 1439-1442CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The synthesis and biol. activity of novel lipoic acid analogs, e.g. I, are reported. Lipoic acid and structural homologs coupled to arylthiophene amidine via carboxamide linkers are metabolic antioxidants capable of protecting neuronal cells against glutamate cytotoxicity, preventing loss of intracellular glutathione, and inhibit nitric oxide synthase.
- 78Dozio, E.; Ruscica, M.; Passafaro, L.; Dogliotti, G.; Steffani, L.; Marthyn, P.; Pagani, A.; Demartini, G.; Esposti, D.; Fraschini, F.; Magni, P. The natural antioxidant alpha-lipoic acid induces p27(Kip1)-dependent cell cycle arrest and apoptosis in MCF-7 human breast cancer cells. Eur. J. Pharmacol. 2010, 641, 29– 34, DOI: 10.1016/j.ejphar.2010.05.009[Crossref], [PubMed], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvVyjsLw%253D&md5=a76d8959f22aab4e35078a95270ba5f0The natural antioxidant alpha-lipoic acid induces p27Kip1-dependent cell cycle arrest and apoptosis in MCF-7 human breast cancer cellsDozio, Elena; Ruscica, Massimiliano; Passafaro, Luca; Dogliotti, Giada; Steffani, Liliana; Pagani, Alessandra; Demartini, Germana; Esposti, Daniele; Fraschini, Franco; Magni, PaoloEuropean Journal of Pharmacology (2010), 641 (1), 29-34CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)Unlike normal cells, tumor cells survive in a specific redox environment where the elevated reactive oxygen species contribute to enhance cell proliferation and to suppress apoptosis. Alpha-lipoic acid, a naturally occurring reactive oxygen species scavenger, has been shown to possess anticancer activity, due to its ability to suppress proliferation and to induce apoptosis in different cancer cell lines. Since at the moment little information is available regarding the potential effects of alpha-lipoic acid on breast cancer, in the present study we addressed the question whether alpha-lipoic acid induces cell cycle arrest and apoptosis in the human breast cancer cell line MCF-7. Moreover, we investigated some mol. mechanisms which mediate alpha-lipoic acid actions, focusing on the role of the PI3-K/Akt signaling pathway. We obsd. that alpha-lipoic acid is able to scavenge reactive oxygen species in MCF-7 cells and that the redn. of reactive oxygen species is followed by cell growth arrest in the G1 phase of the cell cycle, via the specific inhibition of Akt pathway and the up-regulation of the cyclin-dependent kinase inhibitor p27kip1, and by apoptosis, via changes of the ratio of the apoptotic-related protein Bax/Bcl-2. Thus, the antitumor activity of alpha-lipoic acid obsd. in MCF-7 cells further stresses the role of redox state in regulating cancer initiation and progression.
- 79Zhang, S. J.; Ge, Q. F.; Guo, D. W.; Hu, W. X.; Liu, H. Z. Synthesis and anticancer evaluation of α-lipoic acid derivatives. Bioorg. Med. Chem. Lett. 2010, 20, 3078– 3083, DOI: 10.1016/j.bmcl.2010.03.112[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlsFGns78%253D&md5=3bd63422925179c5de11e4bad4e7dcd7Synthesis and anticancer evaluation of α-lipoic acid derivativesZhang, Shi-Jie; Ge, Qiu-Fu; Guo, Dian-Wu; Hu, Wei-Xiao; Liu, Hua-ZhangBioorganic & Medicinal Chemistry Letters (2010), 20 (10), 3078-3083CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)α-Lipoic acid derivs. were synthesized and evaluated for their in vitro anticancer activities against NCI-460, HO-8910, KB, BEL-7402, and PC-3 cell lines. The results, for most compds. exhibited dose-dependent inhibitory property and several compds. had good inhibitions at the dose of 100 μg/mL. Compd. I was further selected for in vivo evaluation against S180 xenograft in ICR mice, which had 24.7% tumor-wt. inhibition through intragastric administration of 200 mg/kg of body wt. Moreover, the LD50 in mice for I through ig exceeded 1000 mg/kg of body wt.
- 80Dorsam, B.; Fahrer, J. The disulfide compound α-lipoic acid and its derivatives: a novel class of anticancer agents targeting mitochondria. Cancer Lett. 2016, 371, 12– 19, DOI: 10.1016/j.canlet.2015.11.019[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28vltVOrtg%253D%253D&md5=46d83c0e531c0482b4c932ac50af950fThe disulfide compound α-lipoic acid and its derivatives: A novel class of anticancer agents targeting mitochondriaDorsam Bastian; Fahrer JorgCancer letters (2016), 371 (1), 12-9 ISSN:.The endogenous disulfide α-lipoic acid (LA) is an essential mitochondrial co-factor. In addition, LA and its reduced counterpart dihydro lipoic acid form a potent redox couple with antioxidative functions, for which it is used as dietary supplement and therapeutic. Recently, it has gained attention due to its cytotoxic effects in cancer cells, which is the key aspect of this review. We initially recapitulate the dietary occurrence, gastrointestinal absorption and pharmacokinetics of LA, illustrating its diverse antioxidative mechanisms. We then focus on its mode of action in cancer cells, in which it triggers primarily the mitochondrial pathway of apoptosis, whereas non-transformed primary cells are hardly affected. Furthermore, LA impairs oncogenic signaling and displays anti-metastatic potential. Novel LA derivatives such as CPI-613, which target mitochondrial energy metabolism, are described and recent pre-clinical studies are presented, which demonstrate that LA and its derivatives exert antitumor activity in vivo. Finally, we highlight clinical studies currently performed with the LA analog CPI-613. In summary, LA and its derivatives are promising candidates to complement the arsenal of established anticancer drugs due to their mitochondria-targeted mode of action and non-genotoxic properties.
- 81Melagraki, G.; Afantitis, A.; Igglessi-Markopoulou, O.; Detsi, A.; Koufaki, M.; Kontogiorgis, C.; Hadjipavlou-Litina, D. J. Synthesis and evaluation of the antioxidant and anti-inflammatory activity of novel coumarin-3-aminoamides and their alpha-lipoic acid adducts. Eur. J. Med. Chem. 2009, 44, 3020– 3026, DOI: 10.1016/j.ejmech.2008.12.027[Crossref], [PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXltl2lur8%253D&md5=d3cbd828bc9bcea1cccde86061fe699fSynthesis and evaluation of the antioxidant and anti-inflammatory activity of novel coumarin-3-aminoamides and their alpha-lipoic acid adductsMelagraki, Georgia; Afantitis, Antreas; Igglessi-Markopoulou, Olga; Detsi, Anastasia; Koufaki, Maria; Kontogiorgis, Christos; Hadjipavlou-Litina, Dimitra J.European Journal of Medicinal Chemistry (2009), 44 (7), 3020-3026CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)In the present work a series of novel coumarin-3-carboxamides, i.e. I, and their hybrids with the alpha-lipoic acid were designed, synthesized and tested as potent antioxidant and anti-inflammatory agents. The new compds. were evaluated for their antioxidant activity, their activity to inhibit in vitro lipoxygenase and their in vivo anti-inflammatory activity. In general, the derivs. were generally found to present antioxidant and anti-inflammatory activities. Discussion is made based on the results for the structure-activity relationships in order to define the structural features required for activity.
- 82Chouinard, G. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J. Clin. Psychiatry 2004, 65 (Suppl. 5), 7– 12[PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjslGqsLs%253D&md5=04d90f92ddd14af6c805b2bf57c54c13Issues in the clinical use of benzodiazepines: Potency, withdrawal, and reboundChouinard, GuyJournal of Clinical Psychiatry (2004), 65 (Suppl. 5), 7-12CODEN: JCLPDE; ISSN:0160-6689. (Physicians Postgraduate Press, Inc.)A review. Low and medium potency benzodiazepines were initially introduced for the treatment of insomnia and anxiety. Their therapeutic actions as anxiolytics, sedative hypnotics, anticonvulsants, and muscle relaxants (with their low toxicity) have led to their use as first-line treatments, and they have become one of the most prescribed classes of drugs. Novel therapeutic uses of benzodiazepines were discovered with the introduction of the high-potency benzodiazepines (e.g., alprazolam, clonazepam, and lorazepam). They were found to be effective in treating panic disorder and panic attacks with or without agoraphobia, as add-on therapy to selective serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder and panic disorders, and as adjunctive therapy in treating patients with acute mania or acute agitation. High-potency benzodiazepines have replaced low and medium potency benzodiazepines in all benzodiazepine clin. indications due to their greater therapeutic effects and rapid onset of action. Differences in distribution, elimination half-life, and rate of absorption are important considerations when choosing a high-potency benzodiazepine. Typically, a benzodiazepine with long distribution and elimination half-lives is preferred. A max. dose of 2 mg/day of any of the high-potency benzodiazepines when given for more than 1 wk is recommended. Although as a class benzodiazepines act rapidly and are well tolerated, their use presents clin. issues such as dependence, rebound anxiety, memory impairment, and discontinuation syndrome.
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- 84Hershon, H. I.; Parsonage, M. Comparative trial of diazepam and pheneturide in treatment of epilepsy. Lancet 1969, 294, 859– 862, DOI: 10.1016/S0140-6736(69)92324-1
- 85Robinson, G. M.; Sellers, E. M. Diazepam withdrawal seizures. Can. Med. Assoc. J. 1982, 126, 944– 945[PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL387otl2rtg%253D%253D&md5=b9b8ed8316d829536001e54cac547e05Diazepam withdrawal seizuresRobinson G M; Sellers E MCanadian Medical Association journal (1982), 126 (8), 944-5 ISSN:0008-4409.There is no expanded citation for this reference.
- 86Devenyi, P.; Harrison, M. L. Prevention of alcohol withdrawal seizures with oral diazepam loading. Can. Med. Assoc. J. 1985, 132, 798– 800[PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M7ltFCmsQ%253D%253D&md5=018cf5c7d636492a064dc985a60d2010Prevention of alcohol withdrawal seizures with oral diazepam loadingDevenyi P; Harrison M LCanadian Medical Association journal (1985), 132 (7), 798-800 ISSN:0008-4409.Twenty patients withdrawing from alcohol who had reliable histories of previous alcohol-withdrawal seizures and thus were at high risk for a subsequent seizure were treated in hospital with oral diazepam loading: 20 mg of the drug was given every hour to a minimum total of 60 mg. None of the patients had a seizure during the stay in hospital. We believe that phenytoin prophylaxis is not necessary in these circumstances. However, if the patient is already taking phenytoin, this drug should not be abruptly discontinued in the withdrawal period in favour of diazepam loading.
- 87Griffin, C. E., 3rd; Kaye, A. M.; Bueno, F. R.; Kaye, A. D. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013, 13, 214– 223[PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sjktlGjsw%253D%253D&md5=c052a8d07f0a07afb4cd42e946a3d3e4Benzodiazepine pharmacology and central nervous system-mediated effectsGriffin Charles E 3rd; Kaye Adam M; Bueno Franklin Rivera; Kaye Alan DThe Ochsner journal (2013), 13 (2), 214-23 ISSN:1524-5012.BACKGROUND: Owing to the low therapeutic index of barbiturates, benzodiazepines (BZDs) became popular in this country and worldwide many decades ago for a wide range of conditions. Because of an increased understanding of pharmacology and physiology, the mechanisms of action of many BZDs are now largely understood, and BZDs of varying potency and duration of action have been developed and marketed. Although BZDs have many therapeutic roles and BZD-mediated effects are typically well tolerated in the general population, side effects and toxicity can result in morbidity and mortality for some patients. The elderly; certain subpopulations of patients with lung, liver, or kidney dysfunction; and patients on other classes of medication are especially prone to toxicity. METHODS: This review details the present knowledge about BZD mechanisms of action, drug profiles, clinical actions, and potential side effects. In addition, this review describes numerous types of BZD-mediated central nervous system effects. CONCLUSION: For any patient taking a BZD, the prescribing physician must carefully evaluate the risks and benefits, and higher-risk patients require careful considerations. Clinically appropriate use of BZDs requires prudence and the understanding of pharmacology.
- 88Calcaterra, N. E.; Barrow, J. C. Classics in chemical neuroscience: diazepam (valium). ACS Chem. Neurosci. 2014, 5, 253– 260, DOI: 10.1021/cn5000056[ACS Full Text], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXis1entr0%253D&md5=0eb7cdab939d38e4eae78714825a495cClassics in Chemical Neuroscience: Diazepam (Valium)Calcaterra, Nicholas E.; Barrow, James C.ACS Chemical Neuroscience (2014), 5 (4), 253-260CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)A review. Diazepam (Valium) is among the most successful drugs from the onset of the psychopharmacol. revolution that began during the 1950s. Efficacious in treating a wide-spectrum of CNS disorders, including anxiety and epilepsy, it set the std. for pharmacotherapy in terms of potency, onset of action, and safety. In this Review, the legacy of diazepam to chem. neuroscience will be considered along with its synthesis, pharmacol., drug metab., adverse events and dependence, clin. use, and regulatory issues.
- 89Hester, J. B., Jr.; Rudzik, A. D.; Kamdar, B. V. 6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines which have central nervous system depressant activity. J. Med. Chem. 1971, 14, 1078– 1081, DOI: 10.1021/jm00293a015[ACS Full Text], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE38Xkt1Snsg%253D%253D&md5=aac07d19e5f37e7327c4e0f5e7855ba86-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines which have central nervous system depressant activityHester, Jackson B., Jr.; Rudzik, Allan D.; Kamdar, Bharat V.Journal of Medicinal Chemistry (1971), 14 (11), 1078-81CODEN: JMCMAR; ISSN:0022-2623.Seventeen 6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines (I) were prepd. by the reaction of 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thiones with carboxylic acid hydrazides. Pharmacol. testing in mice showed that this series had high central depressant activity with low concomitant toxicity. 1-Methyl-6-(o-chlorophenyl)-8-nitro-4H-s-triazolo[4,3-a][1,4]benzodiazepine [33887-02-4] (I, R = Me, R1 = Cl, R2 = H, R3 = NO2) was the most active compd. in the series, being effective in many tests in central depressant activity at doses < 10 μg/kg.
- 90Verster, J. C.; Volkerts, E. R. Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literature. CNS Drug Rev. 2004, 10, 45– 76, DOI: 10.1111/j.1527-3458.2004.tb00003.x[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjtlClu7c%253D&md5=6db5034044ff02a6782b6a132da82062Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literatureVerster, Joris C.; Volkerts, Edmund R.CNS Drug Reviews (2004), 10 (1), 45-76CODEN: CDREFB; ISSN:1080-563X. (Neva Press)A review. Alprazolam is a benzodiazepine deriv. that is currently used in the treatment of generalized anxiety, panic attacks with or without agoraphobia, and depression. Alprazolam has a fast onset of symptom relief (within the first week); it is unlikely to produce dependency or abuse. No tolerance to its therapeutic effect has been reported. At discontinuation of alprazolam treatment, withdrawal and rebound symptoms are common. Hence, alprazolam discontinuation must be tapered. An exhaustive review of the literature showed that alprazolam is significantly superior to placebo, and is at least equally effective in the relief of symptoms as tricyclic antidepressants (TCAs), such as imipramine. However, although alprazolam and imipramine are significantly more effective than placebo in the treatment of panic attacks, Selective Serotonin Reuptake Inhibitors (SSRIs) appear to be superior to either of the two drugs. Therefore, alprazolam is recommended as a second line treatment option, when SSRIs are not effective or well tolerated. In addn. to its therapeutic effects, alprazolam produces adverse effects, such as drowsiness and sedation. Since alprazolam is widely used, many clin. studies investigated its cognitive and psychomotor effects. It is evident from these studies that alprazolam may impair performance in a variety of skills in healthy volunteers as well as in patients. Since the majority of alprazolam users are outpatients, this behavioral impairment limits the safe use of alprazolam in patients routinely engaged in potentially dangerous daily activities, such as driving a car.
- 91de Oliveira, C. S.; Lira, B. F.; Barbosa-Filho, J. M.; Lorenzo, J. G.; de Athayde-Filho, P. F. Synthetic approaches and pharmacological activity of 1,3,4-oxadiazoles: a review of the literature from 2000–2012. Molecules 2012, 17, 10192– 10231, DOI: 10.3390/molecules170910192[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC38bhslSjsA%253D%253D&md5=4f09fb45888e071f2601ff846fc83d9dSynthetic approaches and pharmacological activity of 1,3,4-oxadiazoles: a review of the literature from 2000-2012de Oliveira Cledualdo Soares; Lira Bruno Freitas; Barbosa-Filho Jose Maria; Lorenzo Jorge Goncalo Fernandez; de Athayde-Filho Petronio FilgueirasMolecules (Basel, Switzerland) (2012), 17 (9), 10192-231 ISSN:.This review provides readers with an overview of the main synthetic methodologies for 1,3,4-oxadiazole derivatives, and of their broad spectrum of pharmacological activities as reported over the past twelve years.
- 92Bostrom, J.; Hogner, A.; Llinas, A.; Wellner, E.; Plowright, A. T. Oxadiazoles in medicinal chemistry. J. Med. Chem. 2012, 55, 1817– 1830, DOI: 10.1021/jm2013248[ACS Full Text], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC383pt1Oisw%253D%253D&md5=b934995431ced1be297e6f126262f3cbOxadiazoles in medicinal chemistryBostrom Jonas; Hogner Anders; Llinas Antonio; Wellner Eric; Plowright Alleyn TJournal of medicinal chemistry (2012), 55 (5), 1817-30 ISSN:.Oxadiazoles are five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom, and they exist in different regioisomeric forms. Oxadiazoles are frequently occurring motifs in druglike molecules, and they are often used with the intention of being bioisosteric replacements for ester and amide functionalities. The current study presents a systematic comparison of 1,2,4- and 1,3,4-oxadiazole matched pairs in the AstraZeneca compound collection. In virtually all cases, the 1,3,4-oxadiazole isomer shows an order of magnitude lower lipophilicity (log D), as compared to its isomeric partner. Significant differences are also observed with respect to metabolic stability, hERG inhibition, and aqueous solubility, favoring the 1,3,4-oxadiazole isomers. The difference in profile between the 1,2,4 and 1,3,4 regioisomers can be rationalized by their intrinsically different charge distributions (e.g., dipole moments). To facilitate the use of these heteroaromatic rings, novel synthetic routes for ready access of a broad spectrum of 1,3,4-oxadiazoles, under mild conditions, are described.
- 93Cao, Y.; Min, C.; Acharya, S.; Kim, K. M.; Cheon, S. H. Design, synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligands. Bioorg. Med. Chem. 2016, 24, 191– 200, DOI: 10.1016/j.bmc.2015.12.002[Crossref], [PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVKju7%252FE&md5=75a979afabeb9b2fc0c30e06eea74672Design, synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligandsCao, Yongkai; Min, Chengchun; Acharya, Srijan; Kim, Kyeong-Man; Cheon, Seung HoonBioorganic & Medicinal Chemistry (2016), 24 (2), 191-200CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)The dopamine D3 receptor (D3R) was proposed as a therapeutic target for drug development to treat drug abuse and addiction and neuropsychiatric disorders. Several D3R-selective modulators over the dopamine D2 receptor (D2R) can avoid extrapyramidal symptoms (EPS) and hyperprolactinemia. However, few biased D3R ligands were identified or showed a narrow range of selectivity at the D3R over D2R because of their high sequence homol. Herein, we designed, synthesized and evaluated the binding affinity of a series of bitopic ligands: arypiperazine-phenyl-1,2,4-oxadiazoles. Compd. 9e·HCl was the most potent and selective D3R modulator among these bitopic ligands. Mol. modeling revealed that D3R selectivity depends on the divergence of secondary binding pocket (SBP) in D3R and D2R. Specifically, non-conserved Tyr36, EL1 esp. non-conserved Thr92 and Gly94, and EL2 Val180, Cys181 and Ser182 of D3R may contribute to D3R specificity over D2R.
- 94Mashayekh, S.; Rahmanipour, N.; Mahmoodi, B.; Ahmadi, F.; Motaharian, D.; Shahhosseini, S.; Shafaroodi, H.; Banafshe, H. R.; Shafiee, A.; Navidpour, L. Synthesis, receptor affinity and effect on pentylenetetrazole-induced seizure threshold of novel benzodiazepine analogues: 3-substituted 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles and 2-amino-5-(phenoxybenzyl)-1,3,4-oxadiazoles. Bioorg. Med. Chem. 2014, 22, 1929– 1937, DOI: 10.1016/j.bmc.2014.01.041[Crossref], [PubMed], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisFeisLg%253D&md5=69937663049fafd998edff8b5264a515Synthesis, receptor affinity and effect on pentylenetetrazole-induced seizure threshold of novel benzodiazepine analogues: 3-Substituted 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles and 2-amino-5-(phenoxybenzyl)-1,3,4-oxadiazolesMashayekh, Siavash; Rahmanipour, Narges; Mahmoodi, Behnaz; Ahmadi, Fatemeh; Motaharian, Dina; Shahhosseini, Soraya; Shafaroodi, Hamed; Banafshe, Hamid R.; Shafiee, Abbas; Navidpour, LatifehBioorganic & Medicinal Chemistry (2014), 22 (6), 1929-1937CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)The new series of 5-(2-phenoxybenzyl)-4H-1,2,4-triazoles I (R = SH, SMe, SEt, S-n-Pr, SCH2Ph, OEt, X = H, Cl, F, Y = Y, Cl), possessing C-3 thio, alkylthio and ethoxy substituents, and 2-amino-5-(2-phenoxybenzyl)-1,3,4-oxadiazoles II were designed and synthesized as novel benzodiazepine analogs. Most of them revealed similar to superior binding affinity to the GABAA/benzodiazepine receptor complex, relative to diazepam as the ref. drug. Among them, 5-[4-chloro-2-(2-fluorophenoxy)benzyl]-3-benzylthio-4H-1,2,4-triazole, I (R = SCH2Ph, X = F, Y = Cl), showed the highest affinity (IC50 = 0.892 nM) relative to diazepam (IC50 = 2.857 nM) and also showed the most increase in pentylenetetrazole-induced seizure threshold relative to diazepam as the ref. drug.
- 95Patel, S.; Freedman, S. B. The muscarinic receptor agonist L-658,903 modulates the in vivo accumulation of inositol monophosphates in mouse brain. Eur. J. Pharmacol., Mol. Pharmacol. Sect. 1994, 267, 329– 334, DOI: 10.1016/0922-4106(94)90158-9[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXkt1Kkt78%253D&md5=227f29d2872e8e1ce92b989631ccc1aaThe muscarinic receptor agonist L-658,903 modulates the in vivo accumulation of inositol monophosphates in mouse brainPatel, Shil; Freedman, Stephen B.European Journal of Pharmacology, Molecular Pharmacology Section (1994), 267 (3), 329-34CODEN: EJPPET; ISSN:0922-4106.In the present study the authors examd. the effects of lithium chloride and the muscarinic receptor agonists pilocarpine hydrochloride and L-658,903 (3-(3-methyl-1,2,4-oxadiazol-5-yl) quinuclidine hydrochloride) upon the accumulation of inositol monophosphates in mouse brain using a radiometric technique. Lithium was able to stimulate dose dependently the accumulation of inositol monophosphates with a minimal ED (MED) of 3 mEq/kg s.c. and maximal effect seen at 20 mEq/kg. This corresponded to an increase in the radioactivity in the inositol monophosphate fraction from 1.4±0.06% to 4.6±0.60%. The response was time-dependent, with a peak effect obsd. at 4 h post administration and returning to basal levels by 48 h. The muscarinic receptor agonist pilocarpine (MED 10 mg/kg i.p.) was able to enhance dose dependently the response to 10 mEq/kg lithium, with a max. response seen at 30 mg/kg (9.3% of the total brain radioactivity present in the inositol monophosphate fraction). The efficacious oxadiazole muscarinic receptor agonist L-658,903 also enhanced the response to lithium, producing a maximal effect of 10.4% of the total brain radioactivity present in the inositol monophosphate fraction at 1 mg/kg i.p. This stimulation was blocked by 1 mg/kg scopolamine i.p. but not by 1 mg/kg N-methylscopolamine. These results demonstrate the linkage of muscarinic receptors to the accumulation of inositol monophosphates in vivo, and confirm that following peripheral administration L-658,903 is a potent efficacious agonist at muscarinic receptors within the central nervous system.
- 96Maccioni, E.; Alcaro, S.; Cirilli, R.; Vigo, S.; Cardia, M. C.; Sanna, M. L.; Meleddu, R.; Yanez, M.; Costa, G.; Casu, L.; Matyus, P.; Distinto, S. 3-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles: a new scaffold for the selective inhibition of monoamine oxidase B. J. Med. Chem. 2011, 54, 6394– 6398, DOI: 10.1021/jm2002876[ACS Full Text], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtVegt7zP&md5=0ebf27c64e591293045768508dd61ef83-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles: A new scaffold for the selective inhibition of monoamine oxidase BMaccioni, Elias; Alcaro, Stefano; Cirilli, Roberto; Vigo, Sara; Cardia, Maria Cristina; Sanna, Maria Luisa; Meleddu, Rita; Yanez, Matilde; Costa, Giosue; Casu, Laura; Matyus, Peter; Distinto, SimonaJournal of Medicinal Chemistry (2011), 54 (18), 6394-6398CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)3-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles e. g., I were designed, synthesized, and tested as inhibitors against human monoamine oxidase (MAO) A and B isoforms. Several compds., obtained as racemates, were identified as selective MAO-B inhibitors. The enantiomers of some derivs. were sepd. by enantioselective HPLC and tested. The R-enantiomers always showed the highest activity. Docking study and mol. dynamic simulations demonstrated the putative binding mode. We conclude that these 1,3,4-oxadiazoles derivs. are promising reversible and selective MAO-B inhibitors.
- 97Shook, B. C.; Jackson, P. F. Adenosine A(2A) receptor antagonists and Parkinson’s disease. ACS Chem. Neurosci. 2011, 2, 555– 567, DOI: 10.1021/cn2000537[ACS Full Text], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXosVSrsrc%253D&md5=81746259f96dd1a270f12c3cb2dbe1d3Adenosine A2A Receptor Antagonists and Parkinson's DiseaseShook, Brian C.; Jackson, Paul F.ACS Chemical Neuroscience (2011), 2 (10), 555-567CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)This Review summarizes and updates the work on adenosine A2A receptor antagonists for Parkinson's disease from 2006 to the present. There have been numerous publications, patent applications, and press releases within this time frame that highlight new medicinal chem. approaches to this attractive and promising target to treat Parkinson's disease. The Review is broken down by scaffold type and will discuss the efforts to optimize particular scaffolds for activity, pharmacokinetics, and other drug discovery parameters. The majority of approaches focus on prepg. selective A2A antagonists, but a few approaches to dual A2A/A1 antagonists will also be highlighted. The in vivo profiles of compds. will be highlighted and discussed to compare activities across different chem. series. A clin. report and update will be given on compds. that have entered clin. trials.
- 98Swain, C. J.; Baker, R.; Kneen, C.; Moseley, J.; Saunders, J.; Seward, E. M.; Stevenson, G.; Beer, M.; Stanton, J.; Watling, K. Novel 5-HT3 antagonists. indole oxadiazoles. J. Med. Chem. 1991, 34, 140– 151, DOI: 10.1021/jm00105a021[ACS Full Text], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXkt1Kksg%253D%253D&md5=08f7878a7b8d843a7518288fe4ac7e15Novel 5-HT3 antagonists. Indole oxadiazolesSwain, C. J.; Baker, R.; Kneen, C.; Moseley, J.; Saunders, J.; Seward, E. M.; Stevenson, G.; Beer, M.; Stanton, J.; Watling, K.Journal of Medicinal Chemistry (1991), 34 (1), 140-51CODEN: JMCMAR; ISSN:0022-2623.The synthesis and biochem. evaluation of a series of oxadiazole and indolyloxadiazole 5-HT3 (hydroxytryptamine) antagonists are described. The key pharmacophoric elements have been defined as a basic nitrogen, a linking group capable of H-bonding interactions, and an arom. moiety. The steric limitations of the arom. binding site have been detd. by substitution about the indole ring. Variation of the heterocyclic linking group has shown that while 2 H-bonding interactions are possible, only 1 is essential for high affinity. The environment of the basic nitrogen has been investigated and shown to be optimal when constrained within an azabicyclic system. These results have been incorporated into a proposed binding model for the 5-HT3 antagonist binding site, in which the optimum distance between the arom. binding site and the basic amine is 8.4-8.9 Å and the steric limitations are defined by van der Waals difference mapping.
- 99Rajapakse, H. A.; Nantermet, P. G.; Selnick, H. G.; Munshi, S.; McGaughey, G. B.; Lindsley, S. R.; Young, M. B.; Lai, M. T.; Espeseth, A. S.; Shi, X. P.; Colussi, D.; Pietrak, B.; Crouthamel, M. C.; Tugusheva, K.; Huang, Q.; Xu, M.; Simon, A. J.; Kuo, L.; Hazuda, D. J.; Graham, S.; Vacca, J. P. Discovery of oxadiazoyl tertiary carbinamine inhibitors of β-secretase (BACE-1). J. Med. Chem. 2006, 49, 7270– 7273, DOI: 10.1021/jm061046r[ACS Full Text], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtF2it7fE&md5=ff27839eaa2f89f85fb53a19d3cb32bcDiscovery of Oxadiazoyl Tertiary Carbinamine Inhibitors of β-Secretase (BACE-1)Rajapakse, Hemaka A.; Nantermet, Philippe G.; Selnick, Harold G.; Munshi, Sanjeev; McGaughey, Georgia B.; Lindsley, Stacey R.; Young, Mary Beth; Lai, Ming-Tain; Espeseth, Amy S.; Shi, Xiao-Ping; Colussi, Dennis; Pietrak, Beth; Crouthamel, Ming-Chih; Tugusheva, Katherine; Huang, Qian; Xu, Min; Simon, Adam J.; Kuo, Lawrence; Hazuda, Daria J.; Graham, Samuel; Vacca, Joseph P.Journal of Medicinal Chemistry (2006), 49 (25), 7270-7273CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme β-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.
- 100Pitasse-Santos, P.; Sueth-Santiago, V.; Lima, M. E. F. 1,2,4- and 1,3,4-Oxadiazoles as scaffolds in the development of antiparasitic agents. J. Braz. Chem. Soc. 2018, 29, 435– 456, DOI: 10.21577/0103-5053.20170208[Crossref], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXps1Oqug%253D%253D&md5=21cbe0ccdb4af49b9042c57752afbfa01,2,4- and 1,3,4-oxadiazoles as scaffolds in the development of antiparasitic agentsPitasse-Santos, Paulo; Sueth-Santiago, Vitor; Lima, Marco E. F.Journal of the Brazilian Chemical Society (2018), 29 (3), 435-456CODEN: JOCSET; ISSN:1678-4790. (Sociedade Brasileira de Quimica)In this review, we present the potential use of the heterocyclic oxadiazole rings in the design and synthesis of new drugs to treat parasitic infections. We intend to compare herein all the four isomeric forms of oxadiazole rings as well as discuss the differences and similarities between them. In addn., we discuss aspects on their reactivity that justify the great importance of both 1,2,4- and 1,3,4-oxadiazoles isomers when compared with their other two isomers. Although some oxadiazole isomers satisfy H.ovrddot.uckel's rule, there are differences concerning their aromaticity, which have a great impact on the possible interactions of the oxadiazole ring with biol. receptors. The set of works selected from the literature and discussed herein points out the oxadiazole core as an important and versatile scaffold in the development of new chem. entities potentially useful as antiparasitic drugs.
- 101Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.; Terenius, L.; Luthman, K. Design, synthesis, and evaluation of phe-gly mimetics: heterocyclic building blocks for pseudopeptides. J. Med. Chem. 1999, 42, 4331– 4342, DOI: 10.1021/jm990197+[ACS Full Text], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmt12ltr4%253D&md5=2aa8bee89cec206a816462cfd2d5729bDesign, Synthesis, and Evaluation of Phe-Gly Mimetics: Heterocyclic Building Blocks for PseudopeptidesBorg, Susanna; Vollinga, Roeland C.; Labarre, Maryse; Payza, Kemal; Terenius, Lars; Luthman, KristinaJournal of Medicinal Chemistry (1999), 42 (21), 4331-4342CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Enantiopure heterocyclic Boc-protected Phe-Gly dipeptidomimetics contg. 1,3,4-oxadiazole, 1,2,4-oxadiazole, and 1,2,4-triazole ring systems have been synthesized as building blocks in the synthesis of pseudopeptides. Three derivs. have the carboxylic acid function directly bound to the heterocyclic ring, and three derivs. have an extra methylene group between the heterocyclic ring and the acid function to allow for an increased conformational flexibility. The mimetics were used as Phe-Gly replacements in the biol. active peptides dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) and substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-MetNH2, SP). The pseudopeptide synthesis was performed using solid-phase methodol. on a MBHA-resin using Boc-chem. The biol. evaluation was performed by testing the μ- and δ-opioid receptor affinities of the dermorphin pseudopeptides and the NK1 receptor affinities of the SP pseudopeptides. The results showed that all mimetics except 1,2,4-triazole were excellent replacements of Phe-Gly in dermorphin since they displayed affinities for the μ-receptor (IC50 = 12-31 nM) in the same range as dermorphin itself (IC50 = 6.2 nM). The agonist activity of three pseudopeptides at human μ-receptors was also evaluated. It was shown that the tested compds. retained their agonist activity. The SP pseudopeptides showed considerably lower affinities (IC50 > 1 μM) for the NK1 receptor than SP itself (IC50 = 1.5 nM) indicating that the Phe-Gly replacements prevent the pseudopeptides from adopting bioactive conformations.
- 102Wolfe, M. S. γ-Secretase inhibitors and modulators for Alzheimer’s disease. J. Neurochem. 2012, 120 (Suppl. 1), 89– 98, DOI: 10.1111/j.1471-4159.2011.07501.x[Crossref], [PubMed], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFyns70%253D&md5=f495ec06da422076c7110ea4d0d37bbbγ-secretase inhibitors and modulators for Alzheimer's diseaseWolfe, Michael S.Journal of Neurochemistry (2012), 120 (Suppl. 1), 89-98CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)A review. γ-Secretase is a membrane embedded aspartyl protease complex with presenilin as the catalytic component. Along with β-secretase, this enzyme produces the amyloid β-protein of Alzheimer's disease (AD) from the amyloid β-protein precursor. Because of its key role in the pathogenesis of AD, γ-secretase has been a prime target for drug discovery, and many inhibitors of this protease have been developed. The therapeutic potential of these inhibitors is virtually negated by the fact that γ-secretase is an essential part of the Notch signaling pathway, rendering the compds. unacceptably toxic upon chronic exposure. However, these compds. have served as useful chem. tools for biol. investigations. In contrast, γ-secretase modulators continue to be of keen interest as possible AD therapeutics. These modulators either shift amyloid β-protein prodn. to shorter, less pathogenic peptides or inhibit the proteolysis of amyloid β-protein precursor selectively compared to that of Notch. The various chem. types of inhibitors and modulators will be discussed, along with their use as probes for basic biol. and their potential as AD therapeutics.
- 103Wolfe, M. S. Unlocking truths of γ-secretase in Alzheimer’s disease: what is the translational potential?. Future Neurol. 2014, 9, 419– 429, DOI: 10.2217/fnl.14.35[Crossref], [PubMed], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFymtb7I&md5=4326261d5bcfe4c7d22b1cadd160a650Unlocking truths of γ-secretase in Alzheimer's disease: what is the translational potential?Wolfe, Michael S.Future Neurology (2014), 9 (4), 419-429CODEN: FNUEAM; ISSN:1479-6708. (Future Medicine Ltd.)Considerable evidence, particularly from genetics, points to the aggregation-prone amyloid β-peptide as a pathogenic entity in Alzheimer's disease. Hence, the proteases that produce this peptide from its precursor protein have been prime targets for the development of potential therapeutics. One of these proteases, γ-secretase, has been a particular focus. Many inhibitors and modulators of this membrane-embedded protease complex have been identified, with some brought into late-stage clin. trials, where they have spectacularly failed. The reasons for these failures will be discussed, along with recent findings on the mechanism of γ-secretase and of Alzheimer-causing mutations that may suggest new strategies for targeting this enzyme.
- 104D’Onofrio, G.; Panza, F.; Frisardi, V.; Solfrizzi, V.; Imbimbo, B. P.; Paroni, G.; Cascavilla, L.; Seripa, D.; Pilotto, A. Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer’s disease. Expert Opin. Drug Discovery 2012, 7, 19– 37, DOI: 10.1517/17460441.2012.645534[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1Wjsg%253D%253D&md5=7bb55128f95a0e5d0aa28465cb9e0441Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer's diseaseD'Onofrio, Grazia; Panza, Francesco; Frisardi, Vincenza; Solfrizzi, Vincenzo; Imbimbo, Bruno P.; Paroni, Giulia; Cascavilla, Leandro; Seripa, Davide; Pilotto, AlbertoExpert Opinion on Drug Discovery (2012), 7 (1), 19-37CODEN: EODDBX; ISSN:1746-0441. (Informa Healthcare)A review. Introduction: In an attempt of altering the natural history of Alzheimer's disease (AD), several compds. have been developed with the aim of inhibiting γ-secretase, the enzymic complex generating β-amyloid (Aβ) peptides (Aβ1 - 40 and Aβ1 - 42), from amyloid precursor protein (APP). APP is believed to be involved in the pathophysiol. cascade of AD.Areas covered: This article briefly reviews the profile of γ-secretase inhibitors that have reached the clinic. The paper reviews studies from the primary English literature on γ-secretase inhibitors published before Nov. 2011, searching through the PubMed database of NCBI by author and the following keywords: drugs targeting β-amyloid, γ-secretase inhibitors, dementia syndromes and Alzheimer's disease.Expert opinion: Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concns. However, scanty data are available on the effects of these compds. on brain Aβ deposition after prolonged administration. γ-Secretase inhibitors may cause significant toxicity in exptl. animals and in humans believed to be assocd. with the inhibition of the cleavage of Notch, a transmembrane receptor involved in regulating cell-fate decisions. Unfortunately, two large Phase III clin. trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effects of the drug, possibly due to its lack of selectivity on APP processing. New APP-selective γ-secretase inhibitors are being developed with the hope of overcoming the previous setbacks.
- 105Gillman, K. W.; Starrett, J. E., Jr.; Parker, M. F.; Xie, K.; Bronson, J. J.; Marcin, L. R.; McElhone, K. E.; Bergstrom, C. P.; Mate, R. A.; Williams, R.; Meredith, J. E., Jr.; Burton, C. R.; Barten, D. M.; Toyn, J. H.; Roberts, S. B.; Lentz, K. A.; Houston, J. G.; Zaczek, R.; Albright, C. F.; Decicco, C. P.; Macor, J. E.; Olson, R. E. Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable γ-secretase inhibitor. ACS Med. Chem. Lett. 2010, 1, 120– 124, DOI: 10.1021/ml1000239[ACS Full Text], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjs1WrsL0%253D&md5=f28ebc4be6022fdbe9297c8663588440Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase InhibitorGillman, Kevin W.; Starrett, John E.; Parker, Michael F.; Xie, Kai; Bronson, Joanne J.; Marcin, Lawrence R.; McElhone, Kate E.; Bergstrom, Carl P.; Mate, Robert A.; Williams, Richard; Meredith, Jere E.; Burton, Catherine R.; Barten, Donna M.; Toyn, Jeremy H.; Roberts, Susan B.; Lentz, Kimberley A.; Houston, John G.; Zaczek, Robert; Albright, Charles F.; Decicco, Carl P.; Macor, John E.; Olson, Richard E.ACS Medicinal Chemistry Letters (2010), 1 (3), 120-124CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-β precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compd. 4 is a potent inhibitor of γ-secretase (Aβ40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.
- 106Koufaki, M.; Theodorou, E.; Alexi, X.; Alexis, M. N. Synthesis of a second generation chroman/catechol hybrids and evaluation of their activity in protecting neuronal cells from oxidative stress-induced cell death. Bioorg. Med. Chem. 2010, 18, 3898– 3909, DOI: 10.1016/j.bmc.2010.04.042[Crossref], [PubMed], [CAS], Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmslOis7w%253D&md5=31692e88f11ad931193fad1b42c132b9Synthesis of a second generation chroman/catechol hybrids and evaluation of their activity in protecting neuronal cells from oxidative stress-induced cell deathKoufaki, Maria; Theodorou, Elissavet; Alexi, Xanthippi; Alexis, Michael N.Bioorganic & Medicinal Chemistry (2010), 18 (11), 3898-3909CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)A new generation of chroman/catechol hybrids bearing heterocyclic five-membered rings, such as 1,2,4-oxadiazole 1,3,4-oxadiazole, 1,2,3-triazole, tetrazole and isoxazole, were designed and synthesized. The activity of the new derivs. against oxidative stress induced neuronal damage, was evaluated using glutamate-challenged hippocampal HT22 cells. Compd. 3 in which a 3,4-dimethoxyphenyl moiety, is directly attached to the 1,2,4-oxadiazole ring was the most active among the 2-substituted chroman analogs, with EC50 = 254 ± 65 nM. Concerning the 5-substituted chroman analogs, isoxazole deriv. 29 exhibited the strongest activity (EC50 = 245 ± 38 nM). However, 29 was cytotoxic at concns. higher than 1 μM, while the triazole analog 24 (EC50 = 801 ± 229 nM), was non-toxic at all concns. tested.
- 107Reed, C. W.; Washecheck, J. P.; Quitlag, M. C.; Jenkins, M. T.; Rodriguez, A. L.; Engers, D. W.; Blobaum, A. L.; Jeffrey Conn, P.; Niswender, C. M.; Lindsley, C. W. Surveying heterocycles as amide bioisosteres within a series of mGlu7 NAMs: discovery of VU6019278. Bioorg. Med. Chem. Lett. 2019, 29, 1211– 1214, DOI: 10.1016/j.bmcl.2019.03.016[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmtVCntLg%253D&md5=6d4390eab59aec1506829378170fd4ffSurveying heterocycles as amide bioisosteres within a series of mGlu7 NAMs: Discovery of VU6019278Reed, Carson W.; Washecheck, Jordan P.; Quitlag, Marc C.; Jenkins, Matthew T.; Rodriguez, Alice L.; Engers, Darren W.; Blobaum, Anna L.; Jeffrey Conn, P.; Niswender, Colleen M.; Lindsley, Craig W.Bioorganic & Medicinal Chemistry Letters (2019), 29 (10), 1211-1214CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)This letter describes a diversity-oriented library approach to rapidly assess diverse heterocycles as bioisosteric replacements for a metabolically labile amide moiety within a series of mGlu7 neg. allosteric modulators (NAMs). SAR rapidly honed in on either a 1,2,4- or 1,3,4-oxadizaole ring system as an effective bioisostere for the amide. Further optimization of the southern region of the mGlu7 NAM chemotype led to the discovery of VU6019278, a potent mGlu7 NAM (IC50 = 501 nM, 6.3% L-AP4 Min) with favorable plasma protein binding (rat fu = 0.10), low predicted hepatic clearance (rat CLhep = 27.7 mL/min/kg) and high CNS penetration (rat Kp = 4.9, Kp,uu = 0.65).
- 108Reed, C. W.; McGowan, K. M.; Spearing, P. K.; Stansley, B. J.; Roenfanz, H. F.; Engers, D. W.; Rodriguez, A. L.; Engelberg, E. M.; Luscombe, V. B.; Loch, M. T.; Remke, D. H.; Rook, J. M.; Blobaum, A. L.; Conn, P. J.; Niswender, C. M.; Lindsley, C. W. VU6010608, a novel mGlu7 NAM from a series of N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamides. ACS Med. Chem. Lett. 2017, 8, 1326– 1330, DOI: 10.1021/acsmedchemlett.7b00429[ACS Full Text], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslyrsLzN&md5=56d5c5d5a07a3c823de9be5ee44764c7VU6010608, a Novel mGlu7 NAM from a Series of N-(2-(1H-1,2,4-Triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamidesReed, Carson W.; McGowan, Kevin M.; Spearing, Paul K.; Stansley, Branden J.; Roenfanz, Hanna F.; Engers, Darren W.; Rodriguez, Alice L.; Engelberg, Eileen M.; Luscombe, Vincent B.; Loch, Matthew T.; Remke, Daniel H.; Rook, Jerri M.; Blobaum, Anna L.; Conn, P. Jeffrey; Niswender, Colleen M.; Lindsley, Craig W.ACS Medicinal Chemistry Letters (2017), 8 (12), 1326-1330CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Herein, we report the structure-activity relationships within a series of mGlu7 NAMs based on an N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamide core with excellent CNS penetration (Kp 1.9-5.8 and Kp,uu 0.4-1.4). Analogs in this series displayed steep SAR. Of these, VU6010608 (11a) emerged with robust efficacy in blocking high frequency stimulated long-term potentiation in electrophysiol. studies.
- 109Reed, C. W.; Yohn, S. E.; Washecheck, J. P.; Roenfanz, H. F.; Quitalig, M. C.; Luscombe, V. B.; Jenkins, M. T.; Rodriguez, A. L.; Engers, D. W.; Blobaum, A. L.; Conn, P. J.; Niswender, C. M.; Lindsley, C. W. Discovery of an orally bioavailable and central nervous system (CNS) penetrant mGlu7 negative allosteric modulator (NAM) in vivo tool compound: N-(2-(1 H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962). J. Med. Chem. 2019, 62, 1690– 1695, DOI: 10.1021/acs.jmedchem.8b01810[ACS Full Text], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslCrtA%253D%253D&md5=812a024a3b5708bab2111dfce104fd2eDiscovery of an orally bioavailable and central nervous system (CNS) penetrant mGlu7 negative allosteric modulator (NAM) in vivo tool compound: N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962)Reed, Carson W.; Yohn, Samantha E.; Washecheck, Jordan P.; Roenfanz, Hanna F.; Quitalig, Marc C.; Luscombe, Vincent B.; Jenkins, Matthew T.; Rodriguez, Alice L.; Engers, Darren W.; Blobaum, Anna L.; Conn, P. Jeffrey; Niswender, Colleen M.; Lindsley, Craig W.Journal of Medicinal Chemistry (2019), 62 (3), 1690-1695CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Herein, we report the discovery of a new, orally bioavailable and CNS-penetrant metabotropic glutamate receptor 7 (mGlu7) neg. allosteric modulator I that achieves exposure in cerebral spinal fluid (CSF) 2.5× above the in vitro IC50 at min. EDs (MEDs) of 3 mg/kg in preclin. anxiety models.
- 110Nordhoff, S.; Bulat, S.; Cerezo-Galvez, S.; Hill, O.; Hoffmann-Enger, B.; Lopez-Canet, M.; Rosenbaum, C.; Rummey, C.; Thiemann, M.; Matassa, V. G.; Edwards, P. J.; Feurer, A. The design of potent and selective inhibitors of DPP-4: optimization of ADME properties by amide replacements. Bioorg. Med. Chem. Lett. 2009, 19, 6340– 6345, DOI: 10.1016/j.bmcl.2009.09.078[Crossref], [PubMed], [CAS], Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlWlsrfK&md5=04692309b3fa450f5799446702ecd089The design of potent and selective inhibitors of DPP-4: Optimization of ADME properties by amide replacementsNordhoff, Sonja; Bulat, Stephan; Cerezo-Galvez, Silvia; Hill, Oliver; Hoffmann-Enger, Barbara; Lopez-Canet, Meritxell; Rosenbaum, Claudia; Rummey, Christian; Thiemann, Meinolf; Matassa, Victor G.; Edwards, Paul J.; Feurer, AchimBioorganic & Medicinal Chemistry Letters (2009), 19 (22), 6340-6345CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)For a series of β-homophenylalanine based inhibitors of dipeptidyl peptidase IV, ADME properties were improved by the incorporation of amide replacements. These efforts led to a novel series of potent and selective inhibitors of DPP-4 that exhibit an attractive pharmacokinetic profile and show excellent efficacy in an animal model of diabetes.
- 111Makrilakis, K. The role of DPP-4 inhibitors in the treatment algorithm of type 2 diabetes mellitus: when to select, what to expect. Int. J. Environ. Res. Public Health 2019, 16, 2720, DOI: 10.3390/ijerph16152720[Crossref], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVGmt7vL&md5=246f6f9640899f76ddf54b1abfe0b1c2The role of DPP-4 inhibitors in the treatment algorithm of type 2 diabetes mellitus: when to select, what to expectMakrilakis, KonstantinosInternational Journal of Environmental Research and Public Health (2019), 16 (15), 2720CODEN: IJERGQ; ISSN:1660-4601. (MDPI AG)A review. Type 2 diabetes mellitus is a growing global public health problem, the prevalence of which is projected to increase in the succeeding decades. It is potentially assocd. with many complications, affecting multiple organs and causing a huge burden to the society. Due to its multi-factorial pathophysiol., its treatment is varied and based upon a multitude of pharmacol. agents aiming to tackle the many aspects of the disease pathophysiol. (increasing insulin availability [either through direct insulin administration or through agents that promote insulin secretion], improving sensitivity to insulin, delaying the delivery and absorption of carbohydrates from the gastrointestinal tract, or increasing urinary glucose excretion). DPP-4 (dipeptidyl peptidase-4) inhibitors (or "gliptins") represent a class of oral anti-hyperglycemic agents that inhibit the enzyme DPP-4, thus augmenting the biol. activity of the "incretin" hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) and restoring many of the pathophysiol. problems of diabetes. They have already been used over more than a decade in the treatment of the disease. The current manuscript will review the mechanism of action, therapeutic utility, and the role of DPP-4 inhibitors for the treatment of type 2 diabetes mellitus.
- 112Cao, J.; Zhou, Y.; Peng, H.; Huang, X.; Stahler, S.; Suri, V.; Qadri, A.; Gareski, T.; Jones, J.; Hahm, S.; Perreault, M.; McKew, J.; Shi, M.; Xu, X.; Tobin, J. F.; Gimeno, R. E. Targeting Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases. J. Biol. Chem. 2011, 286, 41838– 41851, DOI: 10.1074/jbc.M111.245456[Crossref], [PubMed], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFaitLbP&md5=fa659203d6b500b82e1a093df2cb40deTargeting Acyl-CoA:Diacylglycerol Acyltransferase 1 (DGAT1) with Small Molecule Inhibitors for the Treatment of Metabolic DiseasesCao, Jingsong; Zhou, Yingjiang; Peng, Haibing; Huang, Xinyi; Stahler, Shannon; Suri, Vipin; Qadri, Ariful; Gareski, Tiffany; Jones, Juli; Hahm, Seung; Perreault, Mylene; McKew, John; Shi, Mengxiao; Xu, Xin; Tobin, James F.; Gimeno, Ruth E.Journal of Biological Chemistry (2011), 286 (48), 41838-41851, S41838/1-S41838/3CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in triglyceride synthesis. Findings from genetically modified mice as well as pharmacol. studies suggest that inhibition of DGAT1 is a promising strategy for the treatment of obesity and type 2 diabetes. Here we characterize a tool DGAT1 inhibitor compd., T863. We found that T863 is a potent inhibitor for both human and mouse DGAT1 in vitro, which acts on the acyl-CoA binding site of DGAT1 and inhibits DGAT1-mediated triacylglycerol formation in cells. In an acute lipid challenge model, oral administration of T863 significantly delayed fat absorption and resulted in lipid accumulation in the distal small intestine of mice, mimicking the effects of genetic ablation of DGAT1. In diet-induced obese mice, oral administration of T863 for 2 wk caused wt. loss, redn. in serum and liver triglycerides, and improved insulin sensitivity. In addn. to the expected triglyceride-lowering activity, T863 also lowered serum cholesterol. Hepatic IRS2 protein was dramatically up-regulated in mice treated with T863, possibly contributing to improved insulin sensitivity. In differentiated 3T3-L1 adipocytes, T863 enhanced insulin-stimulated glucose uptake, suggesting a possible role for adipocytes to improve insulin sensitivity upon DGAT1 inhibition. These results reveal novel mechanistic insights into the insulin-sensitizing effects of DGAT1 inhibition in mouse models. Taken together, our study provides a comprehensive evaluation of a small mol. inhibitor for DGAT1 and suggests that pharmacol. inhibition of DGAT1 holds promise in treating diverse metabolic disorders.
- 113Nakajima, K.; Chatelain, R.; Clairmont, K. B.; Commerford, R.; Coppola, G. M.; Daniels, T.; Forster, C. J.; Gilmore, T. A.; Gong, Y.; Jain, M.; Kanter, A.; Kwak, Y.; Li, J.; Meyers, C. D.; Neubert, A. D.; Szklennik, P.; Tedesco, V.; Thompson, J.; Truong, D.; Yang, Q.; Hubbard, B. K.; Serrano-Wu, M. H. Discovery of an orally bioavailable benzimidazole diacylglycerol acyltransferase 1 (DGAT1) inhibitor that suppresses body weight gain in diet-induced obese dogs and postprandial triglycerides in humans. J. Med. Chem. 2017, 60, 4657– 4664, DOI: 10.1021/acs.jmedchem.7b00173[ACS Full Text], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXns1Wmt7Y%253D&md5=2583c74a8cf9478075df49cacc72864bDiscovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in HumansNakajima, Katsumasa; Chatelain, Ricardo; Clairmont, Kevin B.; Commerford, Renee; Coppola, Gary M.; Daniels, Thomas; Forster, Cornelia J.; Gilmore, Thomas A.; Gong, Yongjin; Jain, Monish; Kanter, Aaron; Kwak, Youngshin; Li, Jingzhou; Meyers, Charles D.; Neubert, Alan D.; Szklennik, Paul; Tedesco, Vivienne; Thompson, James; Truong, David; Yang, Qing; Hubbard, Brian K.; Serrano-Wu, Michael H.Journal of Medicinal Chemistry (2017), 60 (11), 4657-4664CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Modification of a gut restricted class of benzimidazole DGAT1 inhibitor I led to II with good oral bioavailability. The key structural changes to I include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both I and II can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only II was found to be effective in suppressing body wt. gain relative to control in a diet induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body wt. control. II has advanced to clin. investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans.
- 114Serrano-Wu, M. H.; Coppola, G. M.; Gong, Y.; Neubert, A. D.; Chatelain, R.; Clairmont, K. B.; Commerford, R.; Cosker, T.; Daniels, T.; Hou, Y.; Jain, M.; Juedes, M.; Li, L.; Mullarkey, T.; Rocheford, E.; Sung, M. J.; Tyler, A.; Yang, Q.; Yoon, T.; Hubbard, B. K. Intestinally targeted diacylglycerol acyltransferase 1 (DGAT1) inhibitors robustly suppress postprandial triglycerides. ACS Med. Chem. Lett. 2012, 3, 411– 415, DOI: 10.1021/ml3000512[ACS Full Text], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkvFWktLk%253D&md5=4296446fcf69fdf96acf38156c84b950Intestinally Targeted Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors Robustly Suppress Postprandial TriglyceridesSerrano-Wu, Michael H.; Coppola, Gary M.; Gong, Yongjin; Neubert, Alan D.; Chatelain, Ricardo; Clairmont, Kevin B.; Commerford, Renee; Cosker, Theresa; Daniels, Thomas; Hou, Ying; Jain, Monish; Juedes, Marlene; Li, Lisha; Mullarkey, Tara; Rocheford, Erik; Sung, Moo Je; Tyler, Andrew; Yang, Qing; Yoon, Taeyoung; Hubbard, Brian K.ACS Medicinal Chemistry Letters (2012), 3 (5), 411-415CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)High DGAT1 expression levels in the small intestine highlight the crit. role this enzyme plays in nutrient absorption. Identification of inhibitors which predominantly inhibit DGAT1 in the gut is an attractive drug discovery strategy with anticipated benefits of reduced systemic toxicity. In this report we describe our discovery and optimization of DGAT1 inhibitors whose plasma exposure is minimized by the action of transporters, including the P-glycoprotein transporter. The impact of this unique absorption profile on efficacy in rat and dog efficacy models is presented.
- 115Pasquini, S.; Ligresti, A.; Mugnaini, C.; Semeraro, T.; Cicione, L.; De Rosa, M.; Guida, F.; Luongo, L.; De Chiaro, M.; Cascio, M. G.; Bolognini, D.; Marini, P.; Pertwee, R.; Maione, S.; Di Marzo, V.; Corelli, F. Investigations on the 4-quinolone-3-carboxylic acid motif. 3. synthesis, structure-affinity relationships, and pharmacological characterization of 6-substituted 4-quinolone-3-carboxamides as highly selective cannabinoid-2 receptor ligands. J. Med. Chem. 2010, 53, 5915– 5928, DOI: 10.1021/jm100123x[ACS Full Text], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpsVCht78%253D&md5=642a103b93312fd2f1e124173143b656Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 3. Synthesis, Structure-Affinity Relationships, and Pharmacological Characterization of 6-Substituted 4-Quinolone-3-carboxamides as Highly Selective Cannabinoid-2 Receptor LigandsPasquini, Serena; Ligresti, Alessia; Mugnaini, Claudia; Semeraro, Teresa; Cicione, Lavinia; De Rosa, Maria; Guida, Francesca; Luongo, Livio; De Chiaro, Maria; Cascio, Maria Grazia; Bolognini, Daniele; Marini, Pietro; Pertwee, Roger; Maione, Sabatino; Di Marzo, Vincenzo; Corelli, FedericoJournal of Medicinal Chemistry (2010), 53 (16), 5915-5928CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A set of quinolone-3-carboxamides I [R1 = (un)substituted Ph, 2-furyl, 1-cyclohexenyl, 1-isobutylpyrazol-4-yl, etc.; R2 = 1-adamantyl, 1-fenchyl, hexyl, 1-piperidinyl; R3 = pentyl, 1-buten-4-yl, allyl] bearing diverse substituents at position 1, 3, and 6 of the bicyclic nucleus was prepd. Except for six compds. exhibiting Ki > 100 nM, all the quinolone-3-carboxamides I proved to be high affinity CB2 ligands, with Ki values ranging from 73.2 to 0.7 nM and selectivity [SI = Ki(CB1)/Ki(CB2)] varying from >14285 to 1.9, with only one compd. exhibiting a reverse selectivity (SI < 1). In the formalin test of peripheral acute and inflammatory pain in mice, I [R1 = CH2CH2Ph, R2 = 1-adamantyl, R3 = pentyl] showed analgesic activity that was antagonized by a selective CB2 antagonist. By contrast, I [R1 = 2-furyl, R2 = 1-adamantyl, R3 = pentyl] was inactive per se and antagonized the effect of a selective CB2 agonist. Also, two of these compds. exhibited CB2 inverse agonist-like behavior in this in vivo test. However, two different functional assays carried out in vitro indicated for both compds. an overall inverse agonist activity at CB2 receptors.
- 116Pasquini, S.; Botta, L.; Semeraro, T.; Mugnaini, C.; Ligresti, A.; Palazzo, E.; Maione, S.; Di Marzo, V.; Corelli, F. Investigations on the 4-quinolone-3-carboxylic acid motif. 2. synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivo. J. Med. Chem. 2008, 51, 5075– 5084, DOI: 10.1021/jm800552f[ACS Full Text], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptl2htro%253D&md5=5c461877098aec3a53c31676ced30c98Investigations on the 4-quinolone-3-carboxylic acid motif. 2. synthesis and structure-activity relationship of potent and selective cannabinoid-2 receptor agonists endowed with analgesic activity in vivoPasquini, Serena; Botta, Lorenzo; Semeraro, Teresa; Mugnaini, Claudia; Ligresti, Alessia; Palazzo, Enza; Maione, Sabatino; Di Marzo, Vincenzo; Corelli, FedericoJournal of Medicinal Chemistry (2008), 51 (16), 5075-5084CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Quinolone-3-carboxamides bearing at position 5, 6, 7, or 8 diverse substituents such as halides, alkyl, aryl, alkoxy, and aryloxy groups differing in their steric/electronic properties, were prepd. The new compds. were tested in vitro for CB1 and CB2 receptor affinity in comparison with the ref. compds. rimonabant and SR144528. The tested compds. exhibited CB2 affinity in the range from 55.9 to 0.8 nM and CB1 affinity in the range from >10 000 to 5.3 nM, with selectivity indeces [Ki(CB1)/Ki(CB2)] varying from >2666.6 to 1.23. On the basis of the structure-selectivity relationship developed, the presence of a substituent at C6/C8 or C7 well accounts for the high or low CB2 selectivity, resp. Compd. I, characterized by high CB2 affinity and selectivity, showed analgesic activity in the formalin test of acute peripheral and inflammatory pain in mice as a result of selective CB2 agonistic activity.
- 117Pasquini, S.; De Rosa, M.; Pedani, V.; Mugnaini, C.; Guida, F.; Luongo, L.; De Chiaro, M.; Maione, S.; Dragoni, S.; Frosini, M.; Ligresti, A.; Di Marzo, V.; Corelli, F. Investigations on the 4-quinolone-3-carboxylic acid motif. 4. identification of new potent and selective ligands for the cannabinoid type 2 receptor with diverse substitution patterns and antihyperalgesic effects in mice. J. Med. Chem. 2011, 54, 5444– 5453, DOI: 10.1021/jm200476p[ACS Full Text], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXosFCgtbo%253D&md5=4b9daccdccfddbbde2ef53fcca4a87bdInvestigations on the 4-Quinolone-3-carboxylic Acid Motif. 4. Identification of New Potent and Selective Ligands for the Cannabinoid Type 2 Receptor with Diverse Substitution Patterns and Antihyperalgesic Effects in MicePasquini, Serena; De Rosa, Maria; Pedani, Valentina; Mugnaini, Claudia; Guida, Francesca; Luongo, Livio; De Chiaro, Maria; Maione, Sabatino; Dragoni, Stefania; Frosini, Maria; Ligresti, Alessia; Di Marzo, Vincenzo; Corelli, FedericoJournal of Medicinal Chemistry (2011), 54 (15), 5444-5453CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Exptl. evidence suggests that selective CB2 receptor modulators may provide access to antihyperalgesic agents devoid of psychotropic effects. Taking advantage of previous findings on structure-activity/selectivity relationships for a class of 4-quinolone-3-carboxamides, further structural modifications of the heterocyclic scaffold were explored, leading to the discovery of the 8-methoxy deriv. 4a endowed with the highest affinity and selectivity ever reported for a CB2 ligand. The compd., evaluated in vivo in the formalin test, behaved as an inverse agonist by reducing at a dose of 6 mg/kg the second phase of the formalin-induced nocifensive response in mice.
- 118Dundee, J. W.; Halliday, N. J.; Harper, K. W.; Brogden, R. N. Midazolam. a review of its pharmacological properties and therapeutic use. Drugs 1984, 28, 519– 543, DOI: 10.2165/00003495-198428060-00002[Crossref], [PubMed], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXlsFCrtA%253D%253D&md5=50690cc356b140a8c337a883f26d07d5Midazolam. A review of its pharmacological properties and therapeutic useDundee, J. W.; Halliday, N. J.; Harper, K. W.; Brogden, R. N.Drugs (1984), 28 (6), 519-43CODEN: DRUGAY; ISSN:0012-6667.A review with ∼194 refs. on the pharmacodynamics, pharmacokinetics, and therapeutic use of midazolam [59467-70-8].
- 119Gerecke, M. Chemical structure and properties of midazolam compared with other benzodiazepines. Br. J. Clin. Pharmacol. 1983, 16 (Suppl. 1), 11S– 16S, DOI: 10.1111/j.1365-2125.1983.tb02266.x[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXlsFWmt7g%253D&md5=0cee5dcfe1e1dfbe14d189c3b1426ba8Chemical structure and properties of midazolam compared with other benzodiazepinesGerecke, M.British Journal of Clinical Pharmacology (1983), 16 (Suppl. 1), 11-16CODEN: BCPHBM; ISSN:0306-5251.A short review is with 31 refs. on the basic chem. development in the field of "classical" and "annelated" benzodiazepines, distinguishing between pro-drugs and directly acting compds. Some properties of midazolam (I) [59467-70-8] that are of special interest for its practical use are discussed.
- 120Taghizadeh, M. J.; Malakpouri, G. r.; Javidan, A. Improved and scalable methods for the synthesis of midazolam drug and its analogues using isocyanide reagents. J. Iran. Chem. Soc. 2019, 16, 785– 794, DOI: 10.1007/s13738-018-1555-0[Crossref], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFOnur%252FM&md5=c1b88291efb948a2dfc08a8ae558af27Improved and scalable methods for the synthesis of midazolam drug and its analogues using isocyanide reagentsTaghizadeh, Mohammad Javad; malakpouri, Gholam reza; Javidan, AbdollahJournal of the Iranian Chemical Society (2019), 16 (4), 785-794CODEN: JICSCJ; ISSN:1735-207X. (Springer GmbH)Two improved and scalable methods for the synthesis of midazolam and its analogs was described. Midazolam was synthesized using isocyanide reagents in satisfactory yield. In this methodol., imidazobenzodiazepine intermediates were easily prepd. via an improved process. One-pot condensation of benzodiazepines with mono-anion of tosylmethyl isocyanide or Et isocyanoacetate under mild condition led to formation of imidazobenzodiazepine. In the first method, tosylmethyl isocyanide (Tos-MIC) was used and the no. of synthetic steps were decreased in comparison to previous report. In the second method, Et isocyanoacetate which was commonly used for the synthesis of some imidazobenzodiazepines, was consumed to generate midazolam. The latter, a relatively different method for the synthesis of midazolam analogs was reported.
- 121Smith, R.; Brown, J. Midazolam for status epilepticus. Aust. Prescr. 2017, 40, 23– 25, DOI: 10.18773/austprescr.2017.005[Crossref], [PubMed], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czhsFShuw%253D%253D&md5=e97c2ef3121084c1b700fa5fb8455a5fMidazolam for status epilepticusSmith Rob; Brown JanisAustralian prescriber (2017), 40 (1), 23-25 ISSN:0312-8008.There is no expanded citation for this reference.
- 122Vogel, G. W.; Vogel, F. Effect of midazolam on sleep of insomniacs. Br. J. Clin. Pharmacol. 1983, 16 (Suppl. 1), 103S– 108S, DOI: 10.1111/j.1365-2125.1983.tb02279.x
- 123Khanderia, U.; Pandit, S. K. Use of midazolam hydrochloride in anesthesia. Clin. Pharm. 1987, 6, 533– 547[PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1c%252FotFertQ%253D%253D&md5=01e2efd4533e6e595b8848ff225cdc88Use of midazolam hydrochloride in anesthesiaKhanderia U; Pandit S KClinical pharmacy (1987), 6 (7), 533-47 ISSN:0278-2677.The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, dosage, and cost and availability of midazolam hydrochloride are reviewed. The anxiolytic, sedative, hypnotic, anticonvulsant, muscle-relaxant, and amnesic properties of midazolam are similar to those of other injectable benzodiazepines. Midazolam is approximately two to four times as potent as diazepam. Midazolam hydrochloride is water soluble (resulting in fewer local adverse reactions after injection), has a rapid onset and short duration of action, and causes relatively mild cardiovascular and respiratory effects. The drug generally is well tolerated. Midazolam is a good premedicant for general or regional anesthesia. Its greatest use will probably be for conscious sedation during surgical or diagnostic procedures performed under local or regional anesthesia. Induction of anesthesia with midazolam alone is somewhat unpredictable; opiate pretreatment makes induction more consistent. Midazolam is a less reliable induction agent than thiopental, but because it produces fewer adverse cardiovascular and respiratory effects than thiopental, midazolam appears to be a safer induction agent for elderly patients or patients with cardiovascular disease. The recommended dose of midazolam for preoperative sedation is 0.07-0.1 mg/kg given by intramuscular injection one hour before surgery. For conscious sedation, 0.1-0.15 mg/kg intravenously in divided doses is usually adequate. Lower doses of midazolam are recommended for elderly or debilitated patients and patients who have severe liver disease. The costs of equipotent doses of midazolam and injectable diazepam are similar. An oral dosage form is under investigation in the United States. Midazolam's pharmacologic and pharmacokinetic profile makes it an attractive alternative to other injectable benzodiazepines used in anesthesia.
- 124Doods, H.; Arndt, K.; Rudolf, K.; Just, S. CGRP antagonists: unravelling the role of CGRP in migraine. Trends Pharmacol. Sci. 2007, 28, 580– 587, DOI: 10.1016/j.tips.2007.10.005[Crossref], [PubMed], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1KgsLrO&md5=c3295a79a4571c61b56215b0b1760b52CGRP antagonists: unravelling the role of CGRP in migraineDoods, Henri; Arndt, Kirsten; Rudolf, Klaus; Just, StefanTrends in Pharmacological Sciences (2007), 28 (11), 580-587CODEN: TPHSDY; ISSN:0165-6147. (Elsevier B.V.)A review. Migraine is a complex, debilitating neurovascular disorder. Although knowledge on the main mol. players is still incomplete, recent preclin. and clin. findings indicate that there is a clear correlation between migraine-assocd. headache and the release of the neuropeptide calcitonin gene-related peptide (CGRP). BIBN4096 was the first CGRP antagonist to be tested in clin. trials for the treatment of migraine. The proven efficacy of this agent, and also the CGRP antagonist MK-0974, to alleviate acute migraine headache provided significant support for the hypothesis that CGRP has an important role in migraine pathophysiol. Moreover, the recently published results from Phase II trials are encouraging and suggest that this new type of drug might offer advantages over existing therapies for patients suffering from migraine and related headaches.
- 125Bell, I. M. Calcitonin gene-related peptide receptor antagonists: new therapeutic agents for migraine. J. Med. Chem. 2014, 57, 7838– 7858, DOI: 10.1021/jm500364u[ACS Full Text], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVentb7O&md5=ef228d3b829dd642d50eb00e6868ac82Calcitonin Gene-Related Peptide Receptor Antagonists: New Therapeutic Agents for MigraineBell, Ian M.Journal of Medicinal Chemistry (2014), 57 (19), 7838-7858CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Calcitonin gene-related peptide (CGRP) is a potent neuromodulator and vasodilator. It has been implicated in the pathogenesis of migraine by a no. of lines of evidence, although its precise role has yet to be fully defined. Compelling evidence for the importance of CGRP in migraine has been provided by clin. trials with multiple small mol. CGRP receptor antagonists. These clin. studies have shown that blockade of the CGRP receptor can produce antimigraine efficacy comparable to that of the gold std. triptan class of drugs with an incidence of adverse events that appears to be relatively low. The present review describes the discovery and development of these new antimigraine agents and highlights the challenges of identifying orally acting drugs that target a family B G-protein-coupled receptor.
- 126Deen, M.; Correnti, E.; Kamm, K.; Kelderman, T.; Papetti, L.; Rubio-Beltran, E.; Vigneri, S.; Edvinsson, L.; Maassen Van Den Brink, A. Blocking CGRP in migraine patients - a review of pros and cons. J. Headache Pain 2017, 18, 96, DOI: 10.1186/s10194-017-0807-1[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M%252FitlKitA%253D%253D&md5=e78ce644d8a98e89ab1a73a62b16b79dBlocking CGRP in migraine patients - a review of pros and consDeen Marie; Correnti Edvige; Kamm Katharina; Kelderman Tim; Papetti Laura; Rubio-Beltran Eloisa; Maassen Van Den Brink Antoinette; Vigneri Simone; Edvinsson LarsThe journal of headache and pain (2017), 18 (1), 96 ISSN:.Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs. In general, a superior efficacy compared to placebo has been shown, especially with regards to the antibodies. In addition, the efficacy is in line with other currently used prophylactic treatments. The drugs have also been well tolerated, except for some of the gepants, which induced a transient increase in transaminases. Thus, blocking CGRP in migraine patients is seemingly both efficient and well tolerated. However, CGRP and its receptor are abundantly present in both the vasculature, and in the peripheral and central nervous system, and are involved in several physiological processes. Therefore, blocking CGRP may pose a risk in subjects with comorbidities such as cardiovascular diseases. In addition, long-term effects are still unknown. Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones or attenuate wound healing. However, these effects have so far not been reported in human studies. In conclusion, this review suggests that, based on current knowledge, the pros of blocking CGRP in migraine patients exceeds the cons.
- 127Paone, D. V.; Shaw, A. W.; Nguyen, D. N.; Burgey, C. S.; Deng, J. Z.; Kane, S. A.; Koblan, K. S.; Salvatore, C. A.; Mosser, S. D.; Johnston, V. K.; Wong, B. K.; Miller-Stein, C. M.; Hershey, J. C.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Potent, orally bioavailable calcitonin gene-related peptide receptor antagonists for the treatment of migraine: discovery of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1- (2,2,2-trifluoroethyl)azepan-3-yl]-4- (2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin- 1-yl)piperidine-1-carboxamide (MK-0974). J. Med. Chem. 2007, 50, 5564– 5567, DOI: 10.1021/jm070668p[ACS Full Text], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFCisbfO&md5=cd909611a4a4186e112ad16251be997dPotent, Orally Bioavailable Calcitonin Gene-Related Peptide Receptor Antagonists for the Treatment of Migraine: Discovery of N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1- (2,2,2-trifluoroethyl)azepan-3-yl]-4- (2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin- 1-yl)piperidine-1-carboxamide (MK-0974)Paone, Daniel V.; Shaw, Anthony W.; Nguyen, Diem N.; Burgey, Christopher S.; Deng, James Z.; Kane, Stefanie A.; Koblan, Kenneth S.; Salvatore, Christopher A.; Mosser, Scott D.; Johnston, Victor K.; Wong, Bradley K.; Miller-Stein, Cynthia M.; Hershey, James C.; Graham, Samuel L.; Vacca, Joseph P.; Williams, Theresa M.Journal of Medicinal Chemistry (2007), 50 (23), 5564-5567CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure contg. a (3R)-amino-(6S)-phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivs. with lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group, and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities, ultimately leading to clin. candidate 38 (MK-0974).
- 128Salvatore, C. A.; Hershey, J. C.; Corcoran, H. A.; Fay, J. F.; Johnston, V. K.; Moore, E. L.; Mosser, S. D.; Burgey, C. S.; Paone, D. V.; Shaw, A. W.; Graham, S. L.; Vacca, J. P.; Williams, T. M.; Koblan, K. S.; Kane, S. A. Pharmacological characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. J. Pharmacol. Exp. Ther. 2008, 324, 416– 421, DOI: 10.1124/jpet.107.130344[Crossref], [PubMed], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFShtr4%253D&md5=54a6a42dc952f84881cd6e5aebeba0a5Pharmacological characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraineSalvatore, Christopher A.; Hershey, James C.; Corcoran, Halea A.; Fay, John F.; Johnston, Victor K.; Moore, Eric L.; Mosser, Scott D.; Burgey, Christopher S.; Paone, Daniel V.; Shaw, Anthony W.; Graham, Samuel L.; Vacca, Joseph P.; Williams, Theresa M.; Koblan, Kenneth S.; Kane, Stefanie A.Journal of Pharmacology and Experimental Therapeutics (2008), 324 (2), 416-421CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key role in the pathophysiol. of migraine headache. CGRP levels in the cranial circulation are increased during a migraine attack, and CGRP itself has been shown to trigger migraine-like headache. The correlation between CGRP release and migraine headache points to the potential utility of CGRP receptor antagonists as novel therapeutics in the treatment of migraine. Indeed, clin. proof-of-concept in the acute treatment of migraine was demonstrated with an i.v. formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant). Here we report on the pharmacol. characterization of the first orally bioavailable CGRP receptor antagonist in clin. development, MK-0974. In vitro, MK-0974 is a potent antagonist of the human (Ki = 0.77 nM) and rhesus (Ki = 1.2 nM) CGRP receptors but displays >1500-fold lower affinity for the canine and rat receptors as detd. via 125I-human CGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to det. the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concn.-dependent inhibition of dermal vasodilation, generated by capsaicin-induced release of endogenous CGRP, with plasma concns. of 127 and 994 nM required to block 50 and 90% of the blood flow increase, resp. In conclusion, MK-0974 is a highly potent, selective, and orally bioavailable CGRP receptor antagonist, which may be valuable in the acute treatment of migraine.
- 129Paone, D. V.; Nguyen, D. N.; Shaw, A. W.; Burgey, C. S.; Potteiger, C. M.; Deng, J. Z.; Mosser, S. D.; Salvatore, C. A.; Yu, S.; Roller, S.; Kane, S. A.; Selnick, H. G.; Vacca, J. P.; Williams, T. M. Orally bioavailable imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor antagonists: discovery of MK-2918. Bioorg. Med. Chem. Lett. 2011, 21, 2683– 2686, DOI: 10.1016/j.bmcl.2010.12.054[Crossref], [PubMed], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltFKitrc%253D&md5=71e7e25113bfb1b2ebe33dd6b07404e9Orally bioavailable imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor antagonists: Discovery of MK-2918Paone, Daniel V.; Nguyen, Diem N.; Shaw, Anthony W.; Burgey, Christopher S.; Potteiger, Craig M.; Deng, James Z.; Mosser, Scott D.; Salvatore, Christopher A.; Yu, Sean; Roller, Shane; Kane, Stefanie A.; Selnick, Harold G.; Vacca, Joseph P.; Williams, Theresa M.Bioorganic & Medicinal Chemistry Letters (2011), 21 (9), 2683-2686CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compd. with a lower projected clin. dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary Me ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclin. candidate 30 (MK-2918)(I).
- 130Peese, K. M.; Naidu, B. N.; Patel, M.; Li, C.; Langley, D. R.; Terry, B.; Protack, T.; Gali, V.; Lin, Z.; Samanta, H. K.; Zheng, M.; Jenkins, S.; Dicker, I. B.; Krystal, M. R.; Meanwell, N. A.; Walker, M. A. Heterocycle amide isosteres: an approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors. Bioorg. Med. Chem. Lett. 2020, 30, 126784, DOI: 10.1016/j.bmcl.2019.126784[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1eksr3I&md5=671f1b13aa1254656beda5d0fabba062Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitorsPeese, Kevin M.; Narasimhulu Naidu, B.; Patel, Manoj; Li, Chen; Langley, David R.; Terry, Brian; Protack, Tricia; Gali, Volodymyr; Lin, Zeyu; Samanta, Himadri K.; Zheng, Ming; Jenkins, Susan; Dicker, Ira B.; Krystal, Mark R.; Meanwell, Nicholas A.; Walker, Michael A.Bioorganic & Medicinal Chemistry Letters (2020), 30 (3), 126784CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepd. and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety is the optimal amide substitute and the obsd. activity was rationalized using calcd. properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compds. demonstrated moderate clearance and moderate exposure.
- 131Oliveira, M.; Ibanescu, R. I.; Anstett, K.; Mesplede, T.; Routy, J. P.; Robbins, M. A.; Brenner, B. G. The Montreal Primary HIV (PHI) Cohort Study Group; Selective resistance profiles emerging in patient-derived clinical isolates with cabotegravir, bictegravir, dolutegravir, and elvitegravir. Retrovirology 2018, 15, 56, DOI: 10.1186/s12977-018-0440-3[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjsFGntb4%253D&md5=6963c313565df2078500215620e9e84dSelective resistance profiles emerging in patient-derived clinical isolates with cabotegravir, bictegravir, dolutegravir, and elvitegravirOliveira, Maureen; Ibanescu, Ruxandra-Ilinca; Anstett, Kaitlin; Mesplede, Thibault; Routy, Jean-Pierre; Robbins, Marjorie A.; Brenner, Bluma G.Retrovirology (2018), 15 (), 56/1-56/14CODEN: RETRBO; ISSN:1742-4690. (BioMed Central Ltd.)Background: Integrase strand transfer inhibitors (INSTIs) are recommended for first-line HIV therapy based on their relatively high genetic barrier to resistance. Although raltegravir (RAL) and elvitegravir (EVG) resistance profiles are well-characterized, resistance patterns for dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) remain largely unknown. Here, in vitro drug selections compared the development of resistance to DTG, BIC, CAB, EVG and RAL using clin. isolates from treatment-na.ovrddot.ive primary HIV infection (PHI) cohort participants (n = 12), and pNL4.3 recombinant strains encoding patient-derived Integrase with (n = 5) and without (n = 5) the E157Q substitution. Results: Patient-derived viral isolates were serially passaged in PHA-stimulated cord blood mononuclear cells in the presence of escalating concns. of INSTIs over the course of 36-46 wk. Drug resistance arose more rapidly in primary clin. isolates with EVG (12/12), followed by CAB (8/12), DTG (8/12) and BIC (6/12). For pNL4.3 recombinant strains encoding patient-derived integrase, the comparative genetic barrier to resistance was RAL > EVG > CAB > DTG and BIC. The E157Q substitution in integrase delayed the advent of resistance to INSTIs. With EVG, T66I/A, E92G/V/Q, T97A or R263K (n = 16, 3, 2 and 1, resp.) arose by weeks 8-16, followed by 1-4 accessory mutations, conferring high-level resistance (> 100-fold) by week 36. With DTG and BIC, solitary R263K (n = 27), S153F/Y (n = 7) H51Y (n = 2), Q146 R (n = 3) or S147G (n = 1) mutations conferred low-level (< 3-fold) resistance at weeks 36-46. Similarly, most CAB selections (n = 18) resulted in R263K, S153Y, S147G, H51Y, or Q146L solitary mutations. However, three CAB selections resulted in Q148R/K followed by secondary mutations conferring high-level cross-resistance to all INSTIs. EVG-resistant viruses (T66I/R263K, T66I/E157Q/R263K, and S153A/R263K) retained residual susceptibility when switched to DTG, BIC or CAB, losing T66I by week 27. Two EVG-resistant variants developed resistance to DTG, BIC and CAB through the addnl. acquisition of E138A/Q148R and S230N, resp. One EVG-resistant variant (T66I) acquired L74M/ G140S/S147G, L74M/E138K/S147G and H51Y with DTG CAB and BIC, resp. Conclusions: Second generation INSTIs show a higher genetic barrier to resistance than EVG and RAL. The potency of CAB was lower than BIC and DTG. The development of Q148R/K with CAB can result in high-level cross-resistance to all INSTIs.
- 132Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Gonzalez Paz, O.; Hazuda, D. J.; Jones, P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.; Witmer, M. V.; Rowley, M. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J. Med. Chem. 2008, 51, 5843– 5855, DOI: 10.1021/jm800245z[ACS Full Text], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVymtb%252FM&md5=f90f994c7cd031a4063cbb3e91b4c3f0Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS InfectionSumma, Vincenzo; Petrocchi, Alessia; Bonelli, Fabio; Crescenzi, Benedetta; Donghi, Monica; Ferrara, Marco; Fiore, Fabrizio; Gardelli, Cristina; Gonzalez Paz, Odalys; Hazuda, Daria J.; Jones, Philip; Kinzel, Olaf; Laufer, Ralph; Monteagudo, Edith; Muraglia, Ester; Nizi, Emanuela; Orvieto, Federica; Pace, Paola; Pescatore, Giovanna; Scarpelli, Rita; Stillmock, Kara; Witmer, Marc V.; Rowley, MichaelJournal of Medicinal Chemistry (2008), 51 (18), 5843-5855CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these mols. were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclin. species. The good profile of Raltegravir has enabled its progression toward the end of phase III clin. trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.
- 133Naidu, B. N.; Walker, M. A.; Sorenson, M. E.; Ueda, Y.; Matiskella, J. D.; Connolly, T. P.; Dicker, I. B.; Lin, Z.; Bollini, S.; Terry, B. J.; Higley, H.; Zheng, M.; Parker, D. D.; Wu, D.; Adams, S.; Krystal, M. R.; Meanwell, N. A. The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor. Bioorg. Med. Chem. Lett. 2018, 28, 2124– 2130, DOI: 10.1016/j.bmcl.2018.05.027[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvVKjur8%253D&md5=92cf04a143ca99ed7950220c91945e79The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitorNaidu, B. Narasimhulu; Walker, Michael A.; Sorenson, Margaret E.; Ueda, Yasutsugu; Matiskella, John D.; Connolly, Timothy P.; Dicker, Ira B.; Lin, Zeyu; Bollini, Sagarika; Terry, Brian J.; Higley, Helen; Zheng, Ming; Parker, Dawn D.; Wu, Dedong; Adams, Stephen; Krystal, Mark R.; Meanwell, Nicholas A.Bioorganic & Medicinal Chemistry Letters (2018), 28 (12), 2124-2130CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal x-ray structure of compd. 10 (I). It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a satd. C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal x-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclin. profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clin. trials.
- 134Tracz-Gaszewska, Z.; Dobrzyn, P. Stearoyl-CoA desaturase 1 as a therapeutic target for the treatment of cancer. Cancers 2019, 11, 948, DOI: 10.3390/cancers11070948[Crossref], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjtlCksbk%253D&md5=e874e723b747233686121d95448e5898Stearoyl-CoA desaturase 1 as a therapeutic target for the treatment of cancerTracz-Gaszewska, Zuzanna; Dobrzyn, PawelCancers (2019), 11 (7), 948CODEN: CANCCT; ISSN:2072-6694. (MDPI AG)A distinctive feature of cancer cells of various origins involves alterations of the compn. of lipids, with significant enrichment in monounsatd. fatty acids. These mols., in addn. to being structural components of newly formed cell membranes of intensely proliferating cancer cells, support tumorigenic signaling. An increase in the expression of stearoyl-CoA desaturase 1 (SCD1), the enzyme that converts satd. fatty acids to Δ9-monounsatd. fatty acids, has been obsd. in a wide range of cancer cells, and this increase is correlated with cancer aggressiveness and poor outcomes for patients. Studies have demonstrated the involvement of SCD1 in the promotion of cancer cell proliferation, migration, metastasis, and tumor growth. Many studies have reported a role for this lipogenic factor in maintaining the characteristics of cancer stem cells (i.e., the population of cells that contributes to cancer progression and resistance to chemotherapy). Importantly, both the products of SCD1 activity and its direct impact on tumorigenic pathways have been demonstrated. Based on these findings, SCD1 appears to be a significant player in the development of malignant disease and may be a promising target for anticancer therapy. Numerous chem. compds. that exert inhibitory effects on SCD1 have been developed and preclinically tested. The present review summarizes our current knowledge of the ways in which SCD1 contributes to the progression of cancer and discusses opportunities and challenges of using SCD1 inhibitors for the treatment of cancer.
- 135Sun, S.; Zhang, Z.; Kodumuru, V.; Pokrovskaia, N.; Fonarev, J.; Jia, Q.; Leung, P. Y.; Tran, J.; Ratkay, L. G.; McLaren, D. G.; Radomski, C.; Chowdhury, S.; Fu, J.; Hubbard, B.; Winther, M. D.; Dales, N. A. Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseases. Bioorg. Med. Chem. Lett. 2014, 24, 520– 525, DOI: 10.1016/j.bmcl.2013.12.036[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXms1ah&md5=0e63c760d701fe2e88eeb8ff337d0268Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseasesSun, Shaoyi; Zhang, Zaihui; Kodumuru, Vishnumurthy; Pokrovskaia, Natalia; Fonarev, Julia; Jia, Qi; Leung, Po-Yee; Tran, Jennifer; Ratkay, Leslie G.; McLaren, David G.; Radomski, Chris; Chowdhury, Sultan; Fu, Jianmin; Hubbard, Brian; Winther, Michael D.; Dales, Natalie A.Bioorganic & Medicinal Chemistry Letters (2014), 24 (2), 520-525CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Several five- and six-membered heterocycles were introduced to replace the C2-position amide bond of the original 2-aminothiazole-based hit compd. Specifically, replacement of the amide bond with an imidazolidinone moiety yielded a novel and potent thiazolylimidazolidinone series of SCD1 inhibitors. XEN723 I was identified after optimization of the thiazolylimidazolidinone series. This compd. demonstrated a 560-fold improvement in in vitro potency and reduced plasma desatn. indexes in a dose dependent manner, with an EC50 of 4.5 mg/kg.
- 136Ballatore, C.; Huryn, D. M.; Smith, A. B., 3rd Carboxylic acid (bio)isosteres in drug design. ChemMedChem 2013, 8, 385– 395, DOI: 10.1002/cmdc.201200585[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFCms7g%253D&md5=cff8233af1c386439789a0e4ebcb4331Carboxylic Acid (Bio)Isosteres in Drug DesignBallatore, Carlo; Huryn, Donna M.; Smith, Amos B.ChemMedChem (2013), 8 (3), 385-395CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant drawbacks, including metabolic instability, toxicity, as well as limited passive diffusion across biol. membranes. To avoid some of these shortcomings while retaining the desired attributes of the carboxylic acid moiety, medicinal chemists often investigate the use of carboxylic acid (bio)isosteres. The same type of strategy can also be effective for a variety other purposes, for example, to increase the selectivity of a biol. active compd. or to create new intellectual property. Several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this strategy is generally found to be dependent upon the particular context (i.e., the characteristic properties of the drug and the drug-target). As a result, screening of a panel of isosteres is typically required. In this context, the discovery and development of novel carboxylic acid surrogates that could complement the existing palette of isosteres remains an important area of research. The goal of this Minireview is to provide an overview of the most commonly employed carboxylic acid (bio)isosteres and to present representative examples demonstrating the use and utility of each isostere in drug design.
- 137Subramanian, V.; Knight, J. S.; Parelkar, S.; Anguish, L.; Coonrod, S. A.; Kaplan, M. J.; Thompson, P. R. Design, synthesis, and biological evaluation of tetrazole analogs of Cl-amidine as protein arginine deiminase inhibitors. J. Med. Chem. 2015, 58, 1337– 1344, DOI: 10.1021/jm501636x[ACS Full Text], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivFSrsA%253D%253D&md5=f8dbecee72a82061038671d5190635deDesign, Synthesis, and Biological Evaluation of Tetrazole Analogs of Cl-Amidine as Protein Arginine Deiminase InhibitorsSubramanian, Venkataraman; Knight, Jason S.; Parelkar, Sangram; Anguish, Lynne; Coonrod, Scott A.; Kaplan, Mariana J.; Thompson, Paul R.Journal of Medicinal Chemistry (2015), 58 (3), 1337-1344CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Protein arginine deiminases (PADs) catalyze the post-translational hydrolysis of arginine residues to form citrulline. This once obscure modification is now known to play a key role in the etiol. of multiple autoimmune diseases (e.g., rheumatoid arthritis, multiple sclerosis, lupus, and ulcerative colitis) and in some forms of cancer. Among the five human PADs (PAD1, -2, -3, -4, and -6), it is unclear which isoenzyme contributes to disease pathogenesis. Toward the identification of potent, selective, and bioavailable PAD inhibitors that can be used to elucidate the specific roles of each isoenzyme, we describe tetrazole analogs as suitable backbone amide bond bioisosteres for the parent pan PAD inhibitor Cl-amidine. These tetrazole based analogs are highly potent and show selectivity toward particular isoenzymes. Importantly, one of the compds., biphenyl tetrazole tert-Bu Cl-amidine (compd. 13), exhibits enhanced cell killing in a PAD4 expressing osteosarcoma bone marrow (U2OS) cell line and can also block the formation of neutrophil extracellular traps. These bioisosteres represent an important step in our efforts to develop stable, bioavailable, and selective inhibitors for the PADs.
- 138Witalison, E. E.; Thompson, P. R.; Hofseth, L. J. Protein arginine deiminases and associated citrullination: physiological functions and diseases associated with dysregulation. Curr. Drug Targets 2015, 16, 700– 710, DOI: 10.2174/1389450116666150202160954[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFSht7vJ&md5=9d0072b3b5e23308858bb4cd4ed0cab7Protein Arginine Deiminases and Associated Citrullination: Physiological Functions and Diseases Associated with DysregulationWitalison, Erin E.; Thompson, Paul R.; Hofseth, Lorne J.Current Drug Targets (2015), 16 (7), 700-710CODEN: CDTUAU; ISSN:1389-4501. (Bentham Science Publishers Ltd.)Human proteins are subjected to more than 200 known post-translational modifications (PTMs) (e.g., phosphorylation, glycosylation, ubiquitination, S-nitrosylation, methylation, Nacetylation, and citrullination) and these PTMs can alter protein structure and function with consequent effects on the multitude of pathways necessary for maintaining the physiol. homeostasis. When dysregulated, however, the enzymes that catalyze these PTMs can impact the genesis of countless diseases. In this review, we will focus on protein citrullination, a PTM catalyzed by the Protein Arginine Deiminase (PAD) family of enzymes. Specifically, we will describe the roles of the PADs in both normal human physiol. and disease. The development of PAD inhibitors and their efficacy in a variety of autoimmune disorders and cancer will also be discussed.
- 139Leshner, M.; Wang, S.; Lewis, C.; Zheng, H.; Chen, X. A.; Santy, L.; Wang, Y. PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Front. Immunol. 2012, 3, 307, DOI: 10.3389/fimmu.2012.00307[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3s%252Fks1yhtQ%253D%253D&md5=869e8c6330ed07151894fe61b331be8ePAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structuresLeshner Marc; Wang Shu; Lewis Carrie; Zheng Han; Chen Xiangyun Amy; Santy Lorraine; Wang YanmingFrontiers in immunology (2012), 3 (), 307 ISSN:.NETosis, the process wherein neutrophils release highly decondensed chromatin called neutrophil extracellular traps (NETs), has gained much attention as an alternative means of killing bacteria. In vivo, NETs are induced by bacteria and pro-inflammatory cytokines. We have reported that peptidylarginine deiminase 4 (PAD4), an enzyme that converts Arg or monomethyl-Arg to citrulline in histones, is essential for NET formation. The areas of extensive chromatin decondensation along the NETs were rich in histone citrullination. Here, upon investigating the effect of global citrullination in cultured cells, we discovered that PAD4 overexpression in osteosarcoma U2OS cells induces extensive chromatin decondensation independent of apoptosis. The highly decondensed chromatin is released to the extracellular space and stained strongly by a histone citrulline-specific antibody. The structure of the decondensed chromatin is reminiscent of NETs but is unique in that it occurs without stimulation of cells with pro-inflammatory cytokines and bacteria. Furthermore, histone citrullination during chromatin decondensation can dissociate heterochromatin protein 1 beta (HP1β) thereby offering a new molecular mechanism for understanding how citrullination regulates chromatin function. Taken together, our study suggests that PAD4 mediated citrullination induces chromatin decondensation, implicating its essential role in NET formation under physiological conditions in neutrophils.
- 140Khandpur, R.; Carmona-Rivera, C.; Vivekanandan-Giri, A.; Gizinski, A.; Yalavarthi, S.; Knight, J. S.; Friday, S.; Li, S.; Patel, R. M.; Subramanian, V.; Thompson, P.; Chen, P.; Fox, D. A.; Pennathur, S.; Kaplan, M. J. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl. Med. 2013, 5, 178ra40, DOI: 10.1126/scitranslmed.3005580
- 141Han, D.; Handelman, G.; Marcocci, L.; Sen, C. K.; Roy, S.; Kobuchi, H.; Tritschler, H. J.; Flohe, L.; Packer, L. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. BioFactors 1997, 6, 321– 338, DOI: 10.1002/biof.5520060303[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmtVyqu74%253D&md5=87df895d501180c5d14056ff61ccb48aLipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilizationHan, Derick; Handelman, Garry; Marcocci, Lucia; Sen, Chandan K.; Roy, Sashwati; Kobuchi, Hirotsugu; Tritschler, Hans J.; Flohe, Leopold; Packer, LesterBioFactors (1997), 6 (3), 321-338CODEN: BIFAEU; ISSN:0951-6433. (IOS Press)Lipoic acid (thiotic acid) is being used as a dietary supplement, and as a therapeutic agent, and is reported to have beneficial effects in disorders assocd. with oxidative stress, but its mechanism of action remains unclear. We present evidence that lipoic acid induces a substantial increase in cellular reduced glutathione in cultured human Jurkat T cells, human erythrocytes, C6 glial cells, NB41A3 neuroblastoma cells, and peripheral blood lymphocytes. The effect depends on metabolic redn. of lipoic acid to dihydrolipoic acid. Dihydrolipoic acid is released into the culture medium where it reduces cystine. Cysteine thus formed is readily taken up by the neutral amino acid transport system and utilized for glutathione synthesis. By this mechanism lipoic acid enables cystine to bypass the xc- transport system, which is weakly expressed in lymphocytes and inhibited by glutamate. Thereby lipoic acid enables the key enzyme of glutathione synthesis, γ-glutamylcysteine synthetase, which is regulated by uptake-limited cysteine supply, to work at optimum conditions. Flow cytometric anal. of freshly prepd. human peripheral blood lymphocytes, using monobromobimane labeling of cellular thiols, reveals that lipoic acid acts mainly to normalize a subpopulation of cells severely compromised in thiol status rather than to increase thiol content beyond physiol. levels. Hence lipoic acid may have clin. relevance in restoration of severely glutathione deficient cells.
- 142Podda, M.; Tritschler, H. J.; Ulrich, H.; Packer, L. α-lipoic acid supplementation prevents symptoms of vitamin E deficiency. Biochem. Biophys. Res. Commun. 1994, 204, 98– 104, DOI: 10.1006/bbrc.1994.2431[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmsFCnur8%253D&md5=2fb6543fbbc7f90930fa04d3a2af2a6eα-Lipoic acid supplementation prevents symptoms of vitamin E deficiencyPodda, M.; Tritschler, H. J.; Ulrich, H.; Packer, L.Biochemical and Biophysical Research Communications (1994), 204 (1), 98-109CODEN: BBRCA9; ISSN:0006-291X.In this study, using a new animal model for rapid vitamin E deficiency in adult animals and a new technique for tissue extn. of oxidized and reduced α-lipoic acid, we examd. the antioxidant action of α-lipoic acid in vivo. Vitamin E-deficient adult hairless mice displayed obvious symptoms of deficiency with in five weeks, but if the diet was supplemented with α-lipoic acid the animals were completely protected. At five weeks on a vitamin E-deficient diet animals exhibited similar decreases in tissue vitamin E levels, whether supplemented or unsupplemented with α-lipoic acid: vitamin E levels in lvier, kidney, heart, and skin decreased 70 to 85% ppm levels in brain decreased only 25%. These data show that there was no effect of α-lipoic acid supplementation on vitamin E tissue concns., arguing against a role for α-lipoic acid in regenerating vitamin E in vivo.
- 143Rochette, L.; Ghibu, S.; Richard, C.; Zeller, M.; Cottin, Y.; Vergely, C. Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potential. Mol. Nutr. Food Res. 2013, 57, 114– 125, DOI: 10.1002/mnfr.201200608[Crossref], [PubMed], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjslehtw%253D%253D&md5=4692703b1b099b024b1fb4d19c811ab2Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potentialRochette, Luc; Ghibu, Steliana; Richard, Carole; Zeller, Marianne; Cottin, Yves; Vergely, CatherineMolecular Nutrition & Food Research (2013), 57 (1), 114-125CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Diabetes has emerged as a major threat to worldwide health. The exact mechanisms underlying the disease are unknown; however, there is growing evidence that the excess generation of reactive oxygen species (ROS) assocd. with hyperglycemia, causes oxidative stress in a variety of tissues. In this context, various natural compds. with pleiotropic actions like α-lipoic acid (LA) are of interest, esp. in metabolic diseases such as diabetes. LA, either as a dietary supplement or a therapeutic agent, modulates redox potential because of its ability to match the redox status between different subcellular compartments as well as extracellularly. Both the oxidized (disulfide) and reduced (di-thiol: dihydro-lipoic acid, DHLA) forms of LA show antioxidant properties. LA exerts antioxidant effects in biol. systems through ROS quenching but also via an action on transition metal chelation. Dietary supplementation with LA has been successfully employed in a variety of in vivo models of disease assocd. with an imbalance of redox status: diabetes and cardiovascular diseases. The complex and intimate assocn. between increased oxidative stress and increased inflammation in related disorders such as diabetes, makes it difficult to establish the temporal sequence of the relationship.
- 144Koufaki, M.; Kiziridi, C.; Nikoloudaki, F.; Alexis, M. N. Design and synthesis of 1,2-dithiolane derivatives and evaluation of their neuroprotective activity. Bioorg. Med. Chem. Lett. 2007, 17, 4223– 4227, DOI: 10.1016/j.bmcl.2007.05.036[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnsVKnt7c%253D&md5=16d177172281188d616980f44c7b35f1Design and synthesis of 1,2-dithiolane derivatives and evaluation of their neuroprotective activityKoufaki, Maria; Kiziridi, Christina; Nikoloudaki, Faidra; Alexis, Michael N.Bioorganic & Medicinal Chemistry Letters (2007), 17 (15), 4223-4227CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)The authors designed and synthesized new analogs contg. 1,2-dithiolane-3-alkyl and protected or free catechol moieties connected through heteroarom. rings such as triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, tetrazole or thiazole to explore the influence of the bioisosteric replacement of the amide group on the neuroprotective activity of the lipoic acid/dopamine conjugate. Evaluation of the activity of the new compds., using glutamate-challenged hippocampal HT22 cells, showed that incorporation of heteroarom. rings in the alkyl-1,2-dithiolane moieties in conjunction with another antioxidant, in this case catechol, may result in strong neuroprotective activity.
- 145Dani, J. A. Neuronal nicotinic acetylcholine receptor structure and function and response to nicotine. Int. Rev. Neurobiol. 2015, 124, 3– 19, DOI: 10.1016/bs.irn.2015.07.001[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXptlWrtL0%253D&md5=60e9464071be064fd9c669df2f475cbaNeuronal nicotinic acetylcholine receptor structure and function and response to nicotineDani, John A.International Review of Neurobiology (2015), 124 (Nicotine Use in Mental Illness and Neurological Disorders), 3-19CODEN: IRNEAE; ISSN:0074-7742. (Elsevier)Nicotinic acetylcholine receptors (nAChRs) belong to the "Cys-loop" superfamily of ligand-gated ion channels that includes GABAA, glycine, and serotonin (5-HT3) receptors. There are 16 homologous mammalian nAChR subunits encoded by a multigene family. These subunits combine to form many different nAChR subtypes with various expression patterns, diverse functional properties, and differing pharmacol. characteristics. Because cholinergic innervation is pervasive and nAChR expression is extremely broad, practically every area of the brain is impinged upon by nicotinic mechanisms. This review briefly examines the structural and functional properties of the receptor/channel complex Itself. The review also summarizes activation and desensitization of nAChRs by the low nicotine concns. obtained from tobacco. Knowledge of the three-dimensional structure and the structural characteristics of channel gating has reached an advanced stage. Likewise, the basic functional properties of the channel also are reasonably well understood. It is these receptor/channel properties that underlie the participation of nAChRs in nearly every anatomical region of the mammalian brain.
- 146Feduccia, A. A.; Chatterjee, S.; Bartlett, S. E. Neuronal nicotinic acetylcholine receptors: neuroplastic changes underlying alcohol and nicotine addictions. Front. Mol. Neurosci. 2012, 5, 83, DOI: 10.3389/fnmol.2012.00083[Crossref], [PubMed], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Git7zM&md5=6857f2dac6c88f9d336911716c831123Neuronal nicotinic acetylcholine receptors: neuroplastic changes underlying alcohol and nicotine addictionsFeduccia, Allison A.; Chatterjee, Susmita; Bartlett, Selena E.Frontiers in Molecular Neuroscience (2012), 5 (Aug.), 83CODEN: FMNRAJ; ISSN:1662-5099. (Frontiers Media S.A.)A review. Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent mol. mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common mol. target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the mol. and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies.
- 147Buckingham, S. D.; Jones, A. K.; Brown, L. A.; Sattelle, D. B. Nicotinic acetylcholine receptor signalling: roles in Alzheimer’s disease and amyloid neuroprotection. Pharmacol. Rev. 2009, 61, 39– 61, DOI: 10.1124/pr.108.000562[Crossref], [PubMed], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXkvVKjuro%253D&md5=7513d8ea11ac6001401c938d98d0ab84Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotectionBuckingham, Steven D.; Jones, Andrew K.; Brown, Laurence A.; Sattelle, David B.Pharmacological Reviews (2009), 61 (1), 39-61CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. Alzheimer's disease (AD), the major contributor to dementia in the elderly, involves accumulation in the brain of extracellular plaques contg. the β-amyloid protein (Aβ) and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is also characterized by a loss of neurons, particularly those expressing nicotinic acetylcholine receptors (nAChRs), thereby leading to a redn. in nAChR nos. The Aβ1-42 protein, which is toxic to neurons, is crit. to the onset and progression of AD. The discovery of new drug therapies for AD is likely to be accelerated by an improved understanding of the mechanisms whereby Aβ causes neuronal death. We examine the evidence for a role in Aβ1-42 toxicity of nAChRs; paradoxically, nAChRs can also protect neurons when activated by nicotinic ligands. Aβ peptides and nicotine differentially activate several intracellular signaling pathways, including the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog pathway, the extracellular signal-regulated kinase/mitogen-activated protein kinase, and JAK-2/STAT-3 pathways. These pathways control cell death or survival and the secretion of Aβ peptides. We propose that understanding the differential activation of these pathways by nicotine and/or Aβ1-42 may offer the prospect of new routes to therapy for AD.
- 148Woodruff-Pak, D. S.; Gould, T. J. Neuronal nicotinic acetylcholine receptors: involvement in Alzheimer’s disease and schizophrenia. Behav. Cogn. Neurosci. Rev. 2002, 1, 5– 20, DOI: 10.1177/1534582302001001002[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2svps12qtA%253D%253D&md5=a85db74fd91f39e41b17a825662e84aeNeuronal nicotinic acetylcholine receptors: involvement in Alzheimer's disease and schizophreniaWoodruff-Pak Diana S; Gould Thomas JBehavioral and cognitive neuroscience reviews (2002), 1 (1), 5-20 ISSN:1534-5823.Nicotinic acetylcholine receptors (nAChRs) play a role in a variety of diseases of the central nervous system including Alzheimer's disease (AD) and schizophrenia. There is great interest in evaluating disease-related nA ChR changes, and pharmacological treatment of nAChR deficits is a promising therapy. In AD, 7 nAChRs remain relatively stable, contrasting to 4 2 nAChRs that are lost in substantial numbers. -amyloid, a major neuropathology in AD, blocks 4 2 and 7 nAChRs. Agonists selective to 7nAChRs are neuroprotective against--amyloid. Paradoxically, 7nAChRs may function as receptors for -amyloid. These results indicate 7 nAChR antagonists may be appropriate therapy in AD. In schizophrenia, 7 nAChRs are significantly reduced in hippocampus and neocortex. The exceptionally high rate of smoking in schizophrenics is likely a form of self-medication. Therapy with 7 nAChR agonists relieves some schizophrenic symptoms. Despite disparities in etiology and symptomatology, AD and schizophrenia share a target for therapeutic intervention--7 nAChRs.
- 149Beinat, C.; Reekie, T.; Hibbs, D.; Xie, T.; Olson, T. T.; Xiao, Y.; Harvey, A.; O’Connor, S.; Coles, C.; Tsanaktsidis, J.; Kassiou, M. Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333. Eur. J. Med. Chem. 2014, 84, 200– 205, DOI: 10.1016/j.ejmech.2014.07.029[Crossref], [PubMed], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1GrsL7J&md5=5f60b164ac340eec75381dd333c1f465Investigations of amide bond variation and biaryl modification in analogues of α7 nAChR agonist SEN12333Beinat, Corinne; Reekie, Tristan; Hibbs, David; Xie, Teresa; Olson, Thao T.; Xiao, Yingxian; Harvey, Andrew; O'Connor, Susan; Coles, Carolyn; Tsanaktsidis, John; Kassiou, MichaelEuropean Journal of Medicinal Chemistry (2014), 84 (), 200-205CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Several lines of exptl. evidence support the involvement of the α7 nAChR in schizophrenia and Alzheimer's disease. Modulators of the α7 nAChR have been extensively reviewed for the treatment of the cognitive deficits assocd. with these pathologies. SEN12333 represents a novel α7 nAChR agonist chemotype with potential for reduced side effects but requiring further SAR exploration. The present work investigates the amide bond of SEN12333, specifically its connectivity and replacement with the tetrazole functionality, a known cis amide isostere. The results reveal the original amide bond connectivity of SEN12333 to be favorable for binding affinity and agonist activity at α7 nAChRs. The use of a tetrazole isostere completely abolishes affinity and functional activity and suggests that SEN12333 binds in a linear conformation. Results reported herein also suggest the pyridine nitrogen within the terminal arom. ring of SEN12333 is not essential for binding affinity or functional activity. Further SAR investigations involving manipulation of other moieties contained within SEN12333 are warranted.
- 150Haydar, S. N.; Ghiron, C.; Bettinetti, L.; Bothmann, H.; Comery, T. A.; Dunlop, J.; La Rosa, S.; Micco, I.; Pollastrini, M.; Quinn, J.; Roncarati, R.; Scali, C.; Valacchi, M.; Varrone, M.; Zanaletti, R. SAR and biological evaluation of SEN12333/WAY-317538: novel alpha 7 nicotinic acetylcholine receptor agonist. Bioorg. Med. Chem. 2009, 17, 5247– 5258, DOI: 10.1016/j.bmc.2009.05.040[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXosVyqsrk%253D&md5=293ee7e518e64386330cfde5ca72c584SAR and biological evaluation of SEN12333/WAY-317538: Novel alpha 7 nicotinic acetylcholine receptor agonistHaydar, Simon N.; Ghiron, Chiara; Bettinetti, Laura; Bothmann, Hendrick; Comery, Thomas A.; Dunlop, John; La Rosa, Salvatore; Micco, Iolanda; Pollastrini, Martina; Quinn, Joanna; Roncarati, Renza; Scali, Carla; Valacchi, Michela; Varrone, Maurizio; Zanaletti, RiccardoBioorganic & Medicinal Chemistry (2009), 17 (14), 5247-5258CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment assocd. with a variety of disorders including Alzheimer's disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions assocd. with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer's disease. Herein we report a novel, potent small mol. agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compd. is a selective agonist of the α7 nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioral cognition models. The SAR and biol. evaluation of this series of compds. are discussed.
- 151Beinat, C.; Banister, S. D.; van Prehn, S.; Doddareddy, M. R.; Hibbs, D.; Sako, M.; Chebib, M.; Tran, T.; Al-Muhtasib, N.; Xiao, Y.; Kassiou, M. Consequences of linker length alteration of the α7 nicotinic acetylcholine receptor (nAChR) agonist, SEN12333. Bioorg. Med. Chem. Lett. 2012, 22, 2380– 2384, DOI: 10.1016/j.bmcl.2012.02.052[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1yit7s%253D&md5=b17ce649cb8de8749c1f3e0b7c8f1c0cConsequences of linker length alteration of the α7 nicotinic acetylcholine receptor (nAChR) agonist, SEN12333Beinat, Corinne; Banister, Samuel D.; van Prehn, Saundra; Doddareddy, Munikumar Reddy; Hibbs, David; Sako, Michael; Chebib, Mary; Tran, Thao; Al-Muhtasib, Nour; Xiao, Yingxian; Kassiou, MichaelBioorganic & Medicinal Chemistry Letters (2012), 22 (7), 2380-2384CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of ligands based on SEN12333, contg. either contracted or elongated alkyl chains, were synthesized and evaluated in mol. docking studies against a homol. model of the α7 nicotinic acetylcholine receptor (nAChR) subtype. The predicted binding of all ligands was highly similar, with the exception of the analog contg. a 5 methylene unit spacer. However, in vitro competition binding assays revealed that the ligands possessed dissimilar binding affinities, with a Ki range of more than an order of magnitude (Ki = 0.50 to >10 μM), and only SEN12333 itself exhibited functional activity at the α7 nAChR.
- 152Graham, T. H. Prolylcarboxypeptidase (PrCP) inhibitors and the therapeutic uses thereof: a patent review. Expert Opin. Ther. Pat. 2017, 27, 1077– 1088, DOI: 10.1080/13543776.2017.1349104[Crossref], [PubMed], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFKrsbjL&md5=33327e2a7245983dc60f403c31a51313Prolylcarboxypeptidase (PrCP) inhibitors and the therapeutic uses thereof: a patent reviewGraham, Thomas H.Expert Opinion on Therapeutic Patents (2017), 27 (10), 1077-1088CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.): Prolylcarboxypeptidase (PrCP) is a serine protease that produces or degrades signaling proteins in several important pathways including the renin-angiotensin system (RAS), kallikrein-kinin system (KKS) and pro-opiomelanocortin (POMC) system. PrCP has the potential to be a therapeutic target for cardiovascular, inflammatory and metabolic diseases. Numerous classes of PrCP inhibitors have been developed by rational drug design and from high-throughput screening hits. These inhibitors have been tested in mouse models to assess their potential as new therapeutics.:. This review covers the relevant studies that support PrCP as a target for drug discovery. All the significant patent applications and primary literature concerning the development of PrCP inhibitors are discussed. The pathways where PrCP is known to operate are complex and many aspects remain to be characterized. Many potent inhibitors of PrCP have been tested in vivo. The variable results obtained from in vivo studies with PrCP inhibitors suggest that addnl. understanding of the biochem. and the required therapeutic inhibitor levels is necessary. Addnl. fundamental research into the signaling pathways is likely required before the true therapeutic potential of PrCP inhibition will be realized.
- 153Shen, H. C.; Ding, F. X.; Zhou, C.; Xiong, Y.; Verras, A.; Chabin, R. M.; Xu, S.; Tong, X.; Xie, D.; Lassman, M. E.; Bhatt, U. R.; Garcia-Calvo, M. M.; Geissler, W.; Shen, Z.; Chen, D.; Sinharoy, R.; Hale, J. J.; Tata, J. R.; Pinto, S.; Shen, D. M.; Colletti, S. L. Discovery of benzimidazole pyrrolidinyl amides as prolylcarboxypeptidase inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 1299– 1305, DOI: 10.1016/j.bmcl.2011.01.090[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXit1Gmt7w%253D&md5=fd1156e6baf01e5a28a062f56c1d627dDiscovery of benzimidazole pyrrolidinyl amides as prolylcarboxypeptidase inhibitorsShen, Hong C.; Ding, Fa-Xiang; Zhou, Changyou; Xiong, Yusheng; Verras, Andreas; Chabin, Renee M.; Xu, Suoyu; Tong, Xinchun; Xie, Dan; Lassman, Michael E.; Bhatt, Urmi R.; Garcia-Calvo, Margarita M.; Geissler, Wayne; Shen, Zhu; Chen, Dunlu; SinhaRoy, Ranabir; Hale, Jeffery J.; Tata, James R.; Pinto, Shirly; Shen, Dong-Ming; Colletti, Steven L.Bioorganic & Medicinal Chemistry Letters (2011), 21 (5), 1299-1305CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of benzimidazole pyrrolidinyl amides contg. a piperidinyl group were discovered as novel prolylcarboxypeptidase (PrCP) inhibitors. Low-nanomolar IC50's were achieved for several analogs, of which compd. 9b displayed modest ex vivo target engagement in eDIO mouse plasma. Compd. 9b was also studied in vivo for its effect on wt. loss and food intake in an eDIO mouse model and the results will be discussed.
- 154Wu, Z.; Yang, C.; Xiong, Y.; Feng, Z.; Lombardo, M.; Verras, A.; Chabin, R. M.; Xu, S.; Tong, X.; Xie, D.; Lassman, M. E.; Bhatt, U. R.; Garcia-Calvo, M. M.; Geissler, W.; Shen, Z.; Chen, Q.; Sinharoy, R.; Hale, J. J.; Tata, J. R.; Pinto, S.; Shen, D. M.; Colletti, S. L. Discovery of a new class of potent prolylcarboxypeptidase inhibitors derived from alanine. Bioorg. Med. Chem. Lett. 2012, 22, 1774– 1778, DOI: 10.1016/j.bmcl.2011.12.064[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitVWqtbg%253D&md5=1fddce909d175a2c3752bf5e5fdc3856Discovery of a new class of potent prolylcarboxypeptidase inhibitors derived from alanineWu, Zhicai; Yang, Cangming; Xiong, Yusheng; Feng, Zhe; Lombardo, Matthew; Verras, Andreas; Chabin, Renee M.; Xu, Suoyu; Tong, Xinchun; Xie, Dan; Lassman, Mike E.; Bhatt, Urmi R.; Garcia-Calvo, Margarita M.; Geissler, Wayne; Shen, Zhu; Chen, Qing; Sinharoy, Ranabir; Hale, Jeffrey J.; Tata, James R.; Pinto, Shirly; Shen, Dong-Ming; Colletti, Steven L.Bioorganic & Medicinal Chemistry Letters (2012), 22 (4), 1774-1778CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Efforts to modify the central proline portion of lead compd. 4 lead to the discovery of novel prolylcarboxypeptidase (PrCP) inhibitors. Esp., replacement with alanine afforded compd. 19 displaying more potent human and mouse PrCP inhibitory activity than 4 and an overall comparable profile.
- 155Debenham, J. S.; Graham, T. H.; Verras, A.; Zhang, Y.; Clements, M. J.; Kuethe, J. T.; Madsen-Duggan, C.; Liu, W.; Bhatt, U. R.; Chen, D.; Chen, Q.; Garcia-Calvo, M.; Geissler, W. M.; He, H.; Li, X.; Lisnock, J.; Shen, Z.; Tong, X.; Tung, E. C.; Wiltsie, J.; Xu, S.; Hale, J. J.; Pinto, S.; Shen, D. M. Discovery and optimization of orally active cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors. Bioorg. Med. Chem. Lett. 2013, 23, 6228– 6233, DOI: 10.1016/j.bmcl.2013.09.094[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1yqs7bK&md5=4005750b675e71573f7a6167ed843ff8Discovery and optimization of orally active cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitorsDebenham, John S.; Graham, Thomas H.; Verras, Andreas; Zhang, Yong; Clements, Matthew J.; Kuethe, Jeffrey T.; Madsen-Duggan, Christina; Liu, Wensheng; Bhatt, Urmi R.; Chen, Dunlu; Chen, Qing; Garcia-Calvo, Margarita; Geissler, Wayne M.; He, Huaibing; Li, Xiaohua; Lisnock, Jean Marie; Shen, Zhu; Tong, Xinchun; Tung, Elaine C.; Wiltsie, Judyann; Xu, Suoyu; Hale, Jeffrey J.; Pinto, Shirly; Shen, Dong-MingBioorganic & Medicinal Chemistry Letters (2013), 23 (23), 6228-6233CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compds. e. g., I show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose.
- 156Graham, T. H.; Shu, M.; Verras, A.; Chen, Q.; Garcia-Calvo, M.; Li, X.; Lisnock, J.; Tong, X.; Tung, E. C.; Wiltsie, J.; Hale, J. J.; Pinto, S.; Shen, D. M. Pyrazoles as non-classical bioisosteres in prolylcarboxypeptidase (PrCP) inhibitors. Bioorg. Med. Chem. Lett. 2014, 24, 1657– 1660, DOI: 10.1016/j.bmcl.2014.02.070[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXksF2hsL0%253D&md5=52027c184087d4d3f3322031ebe065c0Pyrazoles as non-classical bioisosteres in prolylcarboxypeptidase (PrCP) inhibitorsGraham, Thomas H.; Shu, Min; Verras, Andreas; Chen, Qing; Garcia-Calvo, Margarita; Li, Xiaohua; Lisnock, JeanMarie; Tong, Xinchun; Tung, Elaine C.; Wiltsie, Judyann; Hale, Jeffrey J.; Pinto, Shirly; Shen, Dong-MingBioorganic & Medicinal Chemistry Letters (2014), 24 (7), 1657-1660CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Bioisosteres are integral components of modern pharmaceutical research that allow structural optimization to maximize in vivo efficacy and minimize adverse effects by selectively modifying pharmacodynamic, pharmacokinetic and physicochem. properties. A recent medicinal chem. campaign focused on identifying small mol. inhibitors of prolylcarboxypeptidase (PrCP) initiated an investigation into the use of pyrazoles as bioisosteres for amides. The results indicate that pyrazoles are suitable bioisosteric replacements of amide functional groups. The study is an example of managing bioisosteric replacement by incorporating subsequent structural modifications to maintain potency against the selected target. A heuristic model for an embedded pharmacophore is also described.
- 157Pacher, P.; Batkai, S.; Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 2006, 58, 389– 462, DOI: 10.1124/pr.58.3.2[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVOhtLfO&md5=f54e6d1303645a1c63809879ef2813f3The endocannabinoid system as an emerging target of pharmacotherapyPacher, Pal; Batkai, Sandor; Kunos, GeorgePharmacological Reviews (2006), 58 (3), 389-462CODEN: PAREAQ; ISSN:0031-6997. (American Society for Pharmacology and Experimental Therapeutics)A review. The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metab. and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing no. of physiol. functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathol. conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metab. or transport. The use of selective CB2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of prepns. with controlled compn. and the careful selection of does and route of administration. The growing no. of preclin. studies and clin. trials with compds. that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a no. of diseases for which current treatments do not fully address the patients' need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.
- 158Pertwee, R. G. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos. Trans. R. Soc., B 2012, 367, 3353– 3363, DOI: 10.1098/rstb.2011.0381[Crossref], [PubMed], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVKgtL3L&md5=520dda552cdeb306560444cf7c5932f6Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilitiesPertwee, Roger G.Philosophical Transactions of the Royal Society, B: Biological Sciences (2012), 367 (1607), 3353-3363CODEN: PTRBAE; ISSN:0962-8436. (Royal Society)A review. Human tissues express cannabinoid CB1 and CB2 receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compds. in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB1/CB2 receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ9-tetrahydrocannabinol (Δ9-THC)) and Sativex (Δ9-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible addnl. therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB2 receptors, and/or (v) adjunctive 'multi-targeting'.
- 159Adam, J. M.; Cairns, J.; Caulfield, W.; Cowley, P.; Cumming, I.; Easson, M.; Edwards, D.; Ferguson, M.; Goodwin, R.; Jeremiah, F.; Kiyoi, T.; Mistry, A.; Moir, E.; Morphy, R.; Tierney, J.; York, M.; Baker, J.; Cottney, J. E.; Houghton, A. K.; Westwood, P. J.; Walker, G. Design, synthesis, and structure–activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonists. MedChemComm 2010, 1, 54– 60, DOI: 10.1039/c0md00022a[Crossref], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVeju7vP&md5=0f84b46a18456470f5b4566b9922dbb3Design, synthesis, and structure-activity relationships of indole-3-carboxamides as novel water soluble cannabinoid CB1 receptor agonistsAdam, Julia M.; Cairns, Jim; Caulfield, Wilson; Cowley, Phillip; Cumming, Iain; Easson, Morag; Edwards, Darren; Ferguson, Morag; Goodwin, Richard; Jeremiah, Fiona; Kiyoi, Takao; Mistry, Ashvin; Moir, Elizabeth; Morphy, Richard; Tierney, Jason; York, Mark; Baker, James; Cottney, Jean E.; Houghton, Andrea K.; Westwood, Paul J.; Walker, GlennMedChemComm (2010), 1 (1), 54-60CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A novel CB1 receptor agonist lead series was identified using a high-throughput screening approach. The initial screen afforded a single confirmed hit with poor water soly. Structural variations were explored with the aim of introducing water soly. and improving potency. This led to the discovery of Org 28611, a potent, water sol. CB1 receptor agonist, which was selected for clin. evaluation as a potential i.v. analgesic agent.
- 160Moir, E. M.; Yoshiizumi, K.; Cairns, J.; Cowley, P.; Ferguson, M.; Jeremiah, F.; Kiyoi, T.; Morphy, R.; Tierney, J.; Wishart, G.; York, M.; Baker, J.; Cottney, J. E.; Houghton, A. K.; McPhail, P.; Osprey, A.; Walker, G.; Adam, J. M. Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonists. Bioorg. Med. Chem. Lett. 2010, 20, 7327– 7330, DOI: 10.1016/j.bmcl.2010.10.061[Crossref], [PubMed], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVKjtb%252FP&md5=2cae1c9e1628aed9f86605a2bdc3a99bDesign, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as novel cannabinoid CB1 receptor agonistsMoir, Elizabeth M.; Yoshiizumi, Kazuya; Cairns, Jim; Cowley, Phillip; Ferguson, Morag; Jeremiah, Fiona; Kiyoi, Takao; Morphy, Richard; Tierney, Jason; Wishart, Grant; York, Mark; Baker, James; Cottney, Jean E.; Houghton, Andrea K.; McPhail, Petula; Osprey, Andrew; Walker, Glenn; Adam, Julia M.Bioorganic & Medicinal Chemistry Letters (2010), 20 (24), 7327-7330CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Bicyclic piperazine derivs. were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the abs. configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compds. from metab. by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compd. I demonstrated potent antinociceptive activity in vivo.
- 161Morrison, A. J.; Adam, J. M.; Baker, J. A.; Campbell, R. A.; Clark, J. K.; Cottney, J. E.; Deehan, M.; Easson, A. M.; Fields, R.; Francis, S.; Jeremiah, F.; Keddie, N.; Kiyoi, T.; McArthur, D. R.; Meyer, K.; Ratcliffe, P. D.; Schulz, J.; Wishart, G.; Yoshiizumi, K. Design, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptor. Bioorg. Med. Chem. Lett. 2011, 21, 506– 509, DOI: 10.1016/j.bmcl.2010.10.093[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhs1SqsbjF&md5=5fa07b0b96427490a431477dd708d81eDesign, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptorMorrison, Angus J.; Adam, Julia M.; Baker, James A.; Campbell, Robert A.; Clark, John K.; Cottney, Jean E.; Deehan, Maureen; Easson, Anna-Marie; Fields, Ruth; Francis, Stuart; Jeremiah, Fiona; Keddie, Neil; Kiyoi, Takao; McArthur, Duncan R.; Meyer, Karsten; Ratcliffe, Paul D.; Schulz, Jurgen; Wishart, Grant; Yoshiizumi, KazuyaBioorganic & Medicinal Chemistry Letters (2011), 21 (1), 506-509CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead, a bioisostere approach replacing a piperazine amide with an azole was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of I, which had an increased duration of action in the mouse tail flick test in comparison to the lead compd.
- 162Visse, R.; Nagase, H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 2003, 92, 827– 839, DOI: 10.1161/01.RES.0000070112.80711.3D[Crossref], [PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjtFWqu7c%253D&md5=0fddee610a1b1defa7f60a14a11ae127Matrix metalloproteinases and tissue inhibitors of metalloproteinases. Structure, function, and biochemistryVisse, Robert; Nagase, HideakiCirculation Research (2003), 92 (8), 827-839CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)A review. Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biol. processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration. Currently 23 MMP genes have been identified in humans, and most are multidomain proteins. This review describes the members of the matrixin family and discusses substrate specificity, domain structure and function, the activation of proMMPs, the regulation of matrixin activity by tissue inhibitors of metalloproteinases (TIMPs), and their pathophysiol. implications.
- 163Loffek, S.; Schilling, O.; Franzke, C. W. Series “matrix metalloproteinases in lung health and disease”: biological role of matrix metalloproteinases: a critical balance. Eur. Respir. J. 2011, 38, 191– 208, DOI: 10.1183/09031936.00146510[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3MnksF2ntw%253D%253D&md5=4c4fd9a00410473421a7f942afd0ce38Series "matrix metalloproteinases in lung health and disease": Biological role of matrix metalloproteinases: a critical balanceLoffek S; Schilling O; Franzke C-WThe European respiratory journal (2011), 38 (1), 191-208 ISSN:.Matrix metalloproteinases (MMPs) are members of the metzincin group of proteases which share the conserved zinc-binding motif in their catalytic active site. It was originally thought that their main function is to degrade the various components of the extracellular matrix (ECM), yet recent studies have led us to appreciate their significance as regulators of extracellular tissue signalling networks. Due to the broad spectrum of their substrate specificity, MMPs contribute to the homeostasis of many tissues and participate in several physiological processes, such as bone remodelling, angiogenesis, immunity and wound healing. MMP activity is tightly controlled at the level of transcription, pro-peptide activation and inhibition by tissue inhibitors of MMPs. Dysregulated MMP activity leads to pathological conditions such as arthritis, inflammation and cancer, thus highlighting MMPs as promising therapeutic targets. Analysis of MMP mutant mice has proved to be an essential tool for the identification of novel functions and interactions of single MMP members. Advancing our understanding of the MMP contribution to tissue homeostasis will lead us to identify causal relationships between their dysregulation and the development of disease pathologies, thus guiding us to successful MMP-directed therapies.
- 164Jackson, B. C.; Nebert, D. W.; Vasiliou, V. Update of human and mouse matrix metalloproteinase families. Hum. Genomics 2010, 4, 194– 201, DOI: 10.1186/1479-7364-4-3-194[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpt1yrurY%253D&md5=2151f04ad8848437ee2a03668ccee89eUpdate of human and mouse matrix metalloproteinase familiesJackson, Brian C.; Nebert, Daniel W.; Vasiliou, VasilisHuman Genomics (2010), 4 (3), 194-201CODEN: HGUEAT; ISSN:1479-7364. (Henry Stewart Publications)A review. Matrix metalloproteinases (MMPs) are a family of zinc proteases that degrade most of the components of the extracellular matrix (ECM). MMPs also have a no. of non-traditional roles in processing factors related to cell growth/proliferation, inflammation and more. There are 23 human MMPs and 23 mouse MMPs, most of which share orthol. among most vertebrates; other examples have been found in invertebrates and plants. MMPs are named in order of discovery, but also have been grouped by domain structure or by phylogenetic anal. MMPs are multi-domain proteins which generally contain a signal sequence; propeptide (which keeps the protein inactive until cleaved); catalytic domain; and a hemopexin-like domain (which provides substrate specificity). MMPs are thought to play a role in many disease states, including arthritis, vascular disease, lung injury, wound repair, cancer and various neurodegenerative disorders. Although there has been much clin. interest in MMP inhibitors (MMPIs), few trials have been successful - often due to the broad nature of inhibition and the complex role of different MMPs in a given disease state.
- 165Sheppard, G. S.; Florjancic, A. S.; Giesler, J. R.; Xu, L.; Guo, Y.; Davidsen, S. K.; Marcotte, P. A.; Elmore, I.; Albert, D. H.; Magoc, T. J.; Bouska, J. J.; Goodfellow, C. L.; Morgan, D. W.; Summers, J. B. Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors. Bioorg. Med. Chem. Lett. 1998, 8, 3251– 3256, DOI: 10.1016/S0960-894X(98)00597-6[Crossref], [PubMed], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXht1yn&md5=028737609bba9f565d5377c375ce530aAryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitorsSheppard, George S.; Florjancic, Alan S.; Giesler, Jamie R.; Xu, Lianhong; Guo, Yan; Davidsen, Steven K.; Marcotte, Patrick A.; Elmore, Ildiko; Albert, Daniel H.; Magoc, Terrance J.; Bouska, Jennifer J.; Goodfellow, Carole L.; Morgan, Douglas W.; Summers, James B.Bioorganic & Medicinal Chemistry Letters (1998), 8 (22), 3251-3256CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)A series of succinyl hydroxamate MMP inhibitors (I) were prepd. incorporating an aryl amino ketone moiety in place of the more typical C-terminal amino acid amides. Compds. of the C-terminal ketone series displayed potent inhibition of MMPs. Several compds. of the series were shown to be orally bioavailable.
- 166Sheppard, G. S.; Pireh, D.; Carrera, G. M., Jr.; Bures, M. G.; Heyman, H. R.; Steinman, D. H.; Davidsen, S. K.; Phillips, J. G.; Guinn, D. E.; May, P. D.; Conway, R. D.; Rhein, D. A.; Calhoun, W. C.; Albert, D. H.; Magoc, T. J.; Carter, G. W.; Summers, J. B. 3-(2-(3-Pyridinyl)thiazolidin-4-oyl)indoles, a novel series of platelet activating factor antagonists. J. Med. Chem. 1994, 37, 2011– 2032, DOI: 10.1021/jm00039a015[ACS Full Text], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmvVSmur8%253D&md5=51289cc463fdcbf18b881be8dee1c84b3-(2-(3-Pyridinyl)thiazolidin-4-oyl)indoles, a Novel Series of Platelet Activating Factor AntagonistsSheppard, George S.; Pireh, Daisy; Carrera, George M., Jr.; Bures, Mark G.; Heyman, H. Robin; Steinman, Douglas H.; Davidsen, Steven K.; Phillips, James G.; Guinn, Denise E.; et al.Journal of Medicinal Chemistry (1994), 37 (13), 2011-32CODEN: JMCMAR; ISSN:0022-2623.(2RS,4R)-3-[2-(3-Pyridinyl)thiazolidine-4-carbonyl]indoles represent a new class of potent, orally active antagonists of platelet activating factor (PAF). The compds. were prepd. by acylation of the magnesium or zinc salts of substituted indoles with (2RS,4R)-2-(3-pyridinyl)-3-(tert-butoxycarbonyl)thiazolidine-4-carbonyl chloride. The 3-acylindole moiety functions as a hydrolytically stabilized and conformationally restricted anilide replacement, which imparts a considerable boost in potency to the series. Structure-activity relationships obsd. for substitution on the indole ring system are discussed. Members of the series compare favorably with other reported PAF antagonists.
- 167Sheth, S.; Brito, R.; Mukherjea, D.; Rybak, L. P.; Ramkumar, V. Adenosine receptors: expression, function and regulation. Int. J. Mol. Sci. 2014, 15, 2024– 2052, DOI: 10.3390/ijms15022024[Crossref], [PubMed], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXptVWktrY%253D&md5=64774f90da385624fd6c27531e72e50cAdenosine receptors: expression, function and regulationSheth, Sandeep; Brito, Rafael; Mukherjea, Debashree; Rybak, Leonard P.; Ramkumar, VickramInternational Journal of Molecular Sciences (2014), 15 (2), 2024-2052, 29 pp.CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. Adenosine receptors (ARs) comprise a group of G protein-coupled receptors (GPCR) which mediate the physiol. actions of adenosine. To date, four AR subtypes have been cloned and identified in different tissues. These receptors have distinct localization, signal transduction pathways and different means of regulation upon exposure to agonists. This review will describe the biochem. characteristics and signaling cascade assocd. with each receptor and provide insight into how these receptors are regulated in response to agonists. A key property of some of these receptors is their ability to serve as sensors of cellular oxidative stress, which is transmitted by transcription factors, such as nuclear factor (NF)-κB, to regulate the expression of ARs. Recent observations of oligomerization of these receptors into homo- and hetero-dimers will be discussed. In addn., the importance of these receptors in the regulation of normal and pathol. processes such as sleep, the development of cancers and in protection against hearing loss will be examd.
- 168Carpenter, B.; Lebon, G. Human adenosine A2A receptor: molecular mechanism of ligand binding and activation. Front. Pharmacol. 2017, 8, 898, DOI: 10.3389/fphar.2017.00898[Crossref], [PubMed], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFOhurjL&md5=1190e65842b50865adca6455c318d2a3Human adenosine A2A receptor: molecular mechanism of ligand binding and activationCarpenter, Byron; Lebon, GuillaumeFrontiers in Pharmacology (2017), 8 (), 898/1-898/15CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)A review. Adenosine receptors (ARs) comprise the P1 class of purinergic receptors and belong to the largest family of integral membrane proteins in the human genome, the G protein-coupled receptors (GPCRs). ARs are classified into four subtypes, A1, A2A, A2B, and A3, which are all activated by extracellular adenosine, and play central roles in a broad range of physiol. processes, including sleep regulation, angiogenesis and modulation of the immune system. ARs are potential therapeutic targets in a variety of pathophysiol. conditions, including sleep disorders, cancer, and dementia, which has made them important targets for structural biol. Over a decade of research and innovation has culminated with the publication of more than 30 crystal structures of the human adenosine A2A receptor (A2AR), making it one of the best structurally characterized GPCRs at the at. level. In this review we analyze the structural data reported for A2AR that described for the first time the binding of mode of antagonists, including newly developed drug candidates, synthetic and endogenous agonists, sodium ions and an engineered G protein. These structures have revealed the key conformational changes induced upon agonist and G protein binding that are central to signal transduction by A2AR, and have highlighted both similarities and differences in the activation mechanism of this receptor compared to other class A GPCRs. Finally, comparison of A2AR with the recently solved structures of A1R has provided the first structural insight into the mol. determinants of ligand binding specificity in different AR subtypes.
- 169Pinna, A. Adenosine A2A receptor antagonists in Parkinson’s disease: progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs 2014, 28, 455– 474, DOI: 10.1007/s40263-014-0161-7[Crossref], [PubMed], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXosVWhtLc%253D&md5=1c12ad215ddb2384ec190027d23a3216Adenosine A2A Receptor Antagonists in Parkinson's Disease: Progress in Clinical Trials from the Newly Approved Istradefylline to Drugs in Early Development and Those Already DiscontinuedPinna, AnnalisaCNS Drugs (2014), 28 (5), 455-474CODEN: CNDREF; ISSN:1172-7047. (Springer International Publishing AG)A review. Neurotransmitters other than dopamine, such as norepinephrine, 5-hydroxytryptamine, glutamate, adenosine and acetylcholine, are involved in Parkinson's disease (PD) and contribute to its symptomatol. Thus, the progress of non-dopaminergic therapies for PD has attracted much interest in recent years. Among new classes of drugs, adenosine A2A antagonists have emerged as promising candidates. The development of new highly selective adenosine A2A receptor antagonists, and their encouraging anti-parkinsonian responses in animal models of PD, has provided a rationale for clin. trials to evaluate the therapeutic potential and the safety of these agents in patients with PD. To date, the clin. research regarding A2A antagonists and their potential utilization in PD therapy continues to evolve between drugs just or previously discontinued (preladenant and vipadenant), new derivs. in development (tozadenant, PBF-509, ST1535, ST4206 and V81444) and the relatively old drug istradefylline, which has finally been licensed as an anti-parkinsonian drug in Japan. All these compds. have been shown to have a good safety profile and be well tolerated. Moreover, results from phase II and III trials also demonstrate that A2A antagonists are effective in reducing off-time, without worsening troublesome dyskinesia, and in increasing on-time with a mild increase of non-troublesome dyskinesia, in patients at an advanced stage of PD treated with L-DOPA. In addn., early findings suggest that A2A antagonists might also be efficacious as monotherapy in patients at an early stage of PD. This review summarizes pharmacol. and clin. data available on istradefylline, tozadenant, PBF-509, ST1535, ST4206, V81444, preladenant and vipadenant.
- 170Yang, Z.; Li, X.; Ma, H.; Zheng, J.; Zhen, X.; Zhang, X. Replacement of amide with bioisosteres led to a new series of potent adenosine A2A receptor antagonists. Bioorg. Med. Chem. Lett. 2014, 24, 152– 155, DOI: 10.1016/j.bmcl.2013.11.051[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFOlsLbL&md5=68664c03d577371422198dcd578a157eReplacement of amide with bioisosteres led to a new series of potent adenosine A2A receptor antagonistsYang, Zhaohui; Li, Xuan; Ma, Haikuo; Zheng, Jiyue; Zhen, Xuechu; Zhang, XiaohuBioorganic & Medicinal Chemistry Letters (2014), 24 (1), 152-155CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The authors have previously reported a series of 2,4,6-trisubstituted pyrimidines as potent A2A receptor antagonists. The leading compds. often feature a potentially labile acetamide functional group which tends to hydrolyze under acidic conditions. Here the authors report the replacement of the acetamide functional group with bioisosteres. This effort led the authors to a new series of adenosine A2A receptor antagonists with improved potency and chem. stability.
- 171Stocchi, F.; Rascol, O.; Hauser, R. A.; Huyck, S.; Tzontcheva, A.; Capece, R.; Ho, T. W.; Sklar, P.; Lines, C.; Michelson, D.; Hewitt, D. J. Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease. Neurology 2017, 88, 2198– 2206, DOI: 10.1212/WNL.0000000000004003[Crossref], [PubMed], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1Sntbs%253D&md5=48f46e4057f7435497968585cd93dbabRandomized trial of preladenant, given as monotherapy, in patients with early Parkinson diseaseStocchi, Fabrizio; Rascol, Olivier; Hauser, Robert A.; Huyck, Susan; Tzontcheva, Anjela; Capece, Rachel; Ho, Tony W.; Sklar, Peter; Lines, Christopher; Michelson, David; Hewitt, David J.Neurology (2017), 88 (23), 2198-2206CODEN: NEURAI; ISSN:0028-3878. (Lippincott Williams & Wilkins)Objective: To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy. Methods: This was a randomized, 26-wk, placebo- and active-controlled, parallel-group, multicenter, double-blind trial conducted in adults diagnosed with PD for <5 years who were not yet receiving L-dopa or dopamine agonists. Patients with a Unified Parkinson's Disease Rating Scale (UPDRS) part 3 (motor function) score ≥10 and Hoehn & Yahr score ≤3 were randomized 1:1:1:1:1 to preladenant 2, 5, or 10 mg twice daily, rasagiline 1 mg (active-control) once daily, or placebo. The primary endpoint was the change from baseline at week 26 in the sum of UPDRS parts 2 (activities of daily living) and 3 scores (UPDRS2+3). Results: The no. of patients treated was 1,007. Neither preladenant nor rasagiline was superior to placebo after 26 wk. The differences vs placebo (95% confidence interval) in UPDRS2+3 scores (with a neg. difference indicating improvement vs placebo) were preladenant 2 mg = 2.60 (0.86, 4.30), preladenant 5 mg = 1.30 (-0.41, 2.94), preladenant 10 mg = 0.40 (-1.29, 2.11), and rasagiline 1 mg = 0.30 (-1.35, 2.03). Post hoc analyses did not identify a single causal factor that could explain the finding of a failed trial. Preladenant was generally well-tolerated with few patients discontinuing due to adverse events (preladenant 7%, rasagiline 3%, placebo 4%). Conclusions: No evidence supporting the efficacy of preladenant as monotherapy was obsd. in this phase 3 trial. The lack of efficacy of the active control rasagiline makes it difficult to interpret the results. Clin. trial registration: Clinicaltrials.gov: NCT01155479. Classification of evidence: This study provides Class I evidence that for patients with early PD, preladenant is not effective as monotherapy at the doses studied (2, 5, 10 mg).
- 172Cho, J. H.; Gregersen, P. K. Genomics and the multifactorial nature of human autoimmune disease. N. Engl. J. Med. 2011, 365, 1612– 1623, DOI: 10.1056/NEJMra1100030[Crossref], [PubMed], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsVSrsrbJ&md5=e3614bb47a89912b550e939eda9a91b0Genomics and the multifactorial nature of human autoimmune diseaseCho, Judy H.; Gregersen, Peter K.New England Journal of Medicine (2011), 365 (17), 1612-1623CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)A review on genomewide assocn. studies that are most robust, that most clearly implicate a disease mechanism, or that suggest a new diagnostic or therapeutic approach. For most of these disorders, genes within the major histocompatibility complex (MHC) have by far the strongest single genetic effect, and many of these assocns. have been known for decades. The new genetic findings in autoimmunity are considered in the context of the important contributions of the HLA complex to disease susceptibility and pathogenesis.
- 173Chang, Y.; Xu, S.; Ding, K. Tyrosine kinase 2 (TYK2) allosteric inhibitors to treat autoimmune diseases. J. Med. Chem. 2019, 62, 8951– 8952, DOI: 10.1021/acs.jmedchem.9b01612[ACS Full Text], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFeqtrjK&md5=d8214c7fca197889246df48f29e5c5e5Tyrosine Kinase 2 (TYK2) Allosteric Inhibitors To Treat Autoimmune DiseasesChang, Yu; Xu, Shilin; Ding, KeJournal of Medicinal Chemistry (2019), 62 (20), 8951-8952CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. TYK2 is an emerging drug target for various human autoimmune diseases. However, discovery of selective TYK2 inhibitor over other JAK family members (i.e., JAK1, 2, 3) by targeting the catalytically active site (Janus Homolog 1 (JH1) domain) is challenging. This Viewpoint discusses the discovery of a series of N-Me pyridazine-3-carboxamides as novel selective pseudokinase (JH2) domain binders of TYK2. A systematic structure-based optimization yielded a highly potent and selective allosteric TYK2 inhibitor candidate that is currently in phase III clin. trial for psoriasis.
- 174Liang, J.; Van Abbema, A.; Balazs, M.; Barrett, K.; Berezhkovsky, L.; Blair, W. S.; Chang, C.; Delarosa, D.; DeVoss, J.; Driscoll, J.; Eigenbrot, C.; Goodacre, S.; Ghilardi, N.; MacLeod, C.; Johnson, A.; Bir Kohli, P.; Lai, Y.; Lin, Z.; Mantik, P.; Menghrajani, K.; Nguyen, H.; Peng, I.; Sambrone, A.; Shia, S.; Smith, J.; Sohn, S.; Tsui, V.; Ultsch, M.; Williams, K.; Wu, L. C.; Yang, W.; Zhang, B.; Magnuson, S. Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model. Bioorg. Med. Chem. Lett. 2017, 27, 4370– 4376, DOI: 10.1016/j.bmcl.2017.08.022[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlOku7bJ&md5=d132566f504626660c52c680399c9a09Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis modelLiang, Jun; Van Abbema, Anne; Balazs, Mercedesz; Barrett, Kathy; Berezhkovsky, Leo; Blair, Wade S.; Chang, Christine; Delarosa, Donnie; De Voss, Jason; Driscoll, Jim; Eigenbrot, Charles; Goodacre, Simon; Ghilardi, Nico; MacLeod, Calum; Johnson, Adam; Bir Kohli, Pawan; Lai, Yingjie; Lin, Zhonghua; Mantik, Priscilla; Menghrajani, Kapil; Nguyen, Hieu; Peng, Ivan; Sambrone, Amy; Shia, Steven; Smith, Jan; Sohn, Sue; Tsui, Vickie; Ultsch, Mark; Williams, Karen; Wu, Lawren C.; Yang, Wenqian; Zhang, Birong; Magnuson, StevenBioorganic & Medicinal Chemistry Letters (2017), 27 (18), 4370-4376CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compd. 1. Further optimization led to generation of compd. 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compd. 30 demonstrated dose-dependent redn. of IL-17 prodn. in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a redn. of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.
- 175Baures, P. W.; Ojala, W. H.; Costain, W. J.; Ott, M. C.; Pradhan, A.; Gleason, W. B.; Mishra, R. K.; Johnson, R. L. Design, synthesis, and dopamine receptor modulating activity of diketopiperazine peptidomimetics of L-prolyl-L-leucylglycinamide. J. Med. Chem. 1997, 40, 3594– 3600, DOI: 10.1021/jm970328b[ACS Full Text], [CAS], Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmtlyntLs%253D&md5=157d4fe28293903d9b01891afd50e3f2Design, Synthesis, and Dopamine Receptor-Modulating Activity of Diketopiperazine Peptidomimetics of L-Prolyl-L-leucylglycinamideBaures, Paul W.; Ojala, William H.; Costain, Willard J.; Ott, Michael C.; Gleason, William B.; Mishra, Ram K.; Johnson, Rodney L.Journal of Medicinal Chemistry (1997), 40 (22), 3594-3600CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The diketopiperazine "C5" conformational mimic has been incorporated into the L-prolyl-L-leucylglycinamide (PLG; I) structure and into the bicyclic lactam I-peptidomimetic structure II to give III and IV, resp. These analogs were designed to explore the idea that the N-terminal "C5" conformation, which was found in the crystal structure of V and which was mimicked in VI by the diketopiperazine function, was a factor in the high potency of these two agents. Through the use of the [3H]spiroperidol/N-propylnorapomorphine (NPA) D2 receptor competitive binding assay, both III and IV were found to increase the affinity of the dopamine receptor for agonists and both were found to increase the percentage of D2 receptors which existed in the high-affinity state. These effects were obsd. when Gpp(NH)p was either absent or present, and they were analogous to the effects obsd. previously for I and the I-peptidomimetics V and VI. However, the potency seen with III and IV was less than that seen for V and VI, suggesting that while the N-terminal "C5" conformation may play a role in the potency of the γ-lactam peptidomimetics of I, it does not appear to be the primary factor. In the 6-hydroxydopamine-lesioned animal model of Parkinson's disease, III altered apomorphine-induced rotational behavior in a dose-dependent manner. The max. effect occurred at a dose of 0.01 mg/kg i.p. and resulted in a 52.27 ± 13.96% (p < 0.001, n = 7) increase in rotations compared to apomorphine administered alone.
- 176Chiu, S.; Paulose, C. S.; Mishra, R. K. Effect of L-prolyl-L-leucyl-glycinamide (PLG) on neuroleptic-induced catalepsy and dopamine/neuroleptic receptor bindings. Peptides 1981, 2, 105– 111, DOI: 10.1016/S0196-9781(81)80019-8[Crossref], [PubMed], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXhs1yntbk%253D&md5=bb5761c2f994899475efdbee3d344c93Effect of L-prolyl-L-leucylglycinamide (PLG) on neuroleptic-induced catalepsy and dopamine/neuroleptic receptor bindingsChiu, Simon; Paulose, C. S.; Mishra, Ram K.Peptides (New York, NY, United States) (1981), 2 (1), 105-11CODEN: PPTDD5; ISSN:0196-9781.The mechanism of action subserving the potential antiParkinsonian properties of L-prolyl-L-leucyl-glycinamide (PLG) [2002-44-0] was investigated in behavioral and neurochem. models of dopaminergic function in the rat. Acute administration of PLG (20 and 40 mg/kg s.c.) failed to alter appreciably the intensity of the cateleptic response elicited by haloperidol [52-86-8] (3 mg/kg i.p.). By contrast, chronic PLG treatment (20, 40 and 80 mg/kg s.c.-twice daily for 5 days) significantly attenuated haloperidol-induced catalepsy. The effect of PLG on in vitro dopamine/neuroleptic receptor binding in rat striatum as differently labeled by apomorphine [58-00-4] and spiroperidol was also examd. PLG selectively enhanced the affinity of the sp. binding of agonist [3H]apomorphine to dopamine receptors in the striatum, but had no effect on 3H labeled spiroperidol [749-02-0] binding. Apparently, PLG may facilitate nigro-striatal dopaminergic neurotransmission through interacting with a unique PLG receptor functionally coupled to the dopamine receptor-adenylate cyclase complex.
- 177Srivastava, L. K.; Bajwa, S. B.; Johnson, R. L.; Mishra, R. K. Interaction of L-prolyl-L-leucyl glycinamide with dopamine D2 receptor: evidence for modulation of agonist affinity states in bovine striatal membranes. J. Neurochem. 1988, 50, 960– 968, DOI: 10.1111/j.1471-4159.1988.tb03005.x[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXht1Gjurs%253D&md5=cb868b612e75938ae1a317938f949cbaInteraction of L-prolyl-L-leucyl glycinamide with dopamine D2 receptor: evidence for modulation of agonist affinity states in bovine striatal membranesSrivastava, Lalit K.; Bajwa, Samina B.; Johnson, Rodney L.; Mishra, Ram K.Journal of Neurochemistry (1988), 50 (3), 960-8CODEN: JONRA9; ISSN:0022-3042.The role of the hypothalamic tripeptide L-prolyl-L-leucyl-glycinamide (PLG) in modulating the agonist binding to bovine striatal dopamine D2 receptor was investigated using a selective high-affinity agonist, propylnorapomorphine (NPA). PLG caused an enhancement in [3H]NPA binding in striatal membranes in a dose-dependent manner, the max. effect being obsd. at 10-7-10-6M PLG. The Scatchard anal. of [3H]NPA binding to membranes preincubated with 10-6M PLG revealed an increase in the affinity of the agonist binding sites. In contrast, there was no effect of PLG on the binding pattern of the antagonist [3H]spiroperidol. The antagonist vs. agonist competition curves analyzed for agonist high- and low-affinity states of the receptor displayed an increase in the population and affinity of the high-affinity form of the receptor with PLG treatment. The low-affinity sites concomitantly decreased with relatively small change in the affinity for the agonists. Almost similar results were obtained when either NPA or apomorphine was used in the competition expts. A partial antagonistic effect of PLG on Gpp(NH)p-induced inhibition of high-affinity agonist binding was also obsd., as the ratio of high- to low-affinity forms of the receptor was higher in the PLG-treated membranes compared to the controls. Direct [3H]NPA binding expts. demonstrated that PLG attenuated the Gpp(NH)p-induced inhibition of agonist binding by increasing the EC50 of the nucleotide (concn. that inhibits 50% of the specific binding). No effect of PLG on high-affinity [3H]NPA binding, however, was obsd. when the striatal membranes were preincubated with Gpp(NH)p. The binding of antagonists and agonists to α2 adrenergic receptors, neg. coupled to adenylate cyclase in the striatum, was not affected by PLG. Apparently, PLG modulates the affinity states of the dopamine D2 receptor, possibly by enhancing its interaction with the guanine nucleotide regulatory protein.
- 178Baures, P. W.; Ojala, W. H.; Gleason, W. B.; Mishra, R. K.; Johnson, R. L. Design, synthesis, X-ray analysis, and dopamine receptor-modulating activity of mimics of the ″C5″ hydrogen-bonded conformation in the peptidomimetic 2-oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1-pyrrolidineacetamide. J. Med. Chem. 1994, 37, 3677– 3683, DOI: 10.1021/jm00048a003[ACS Full Text], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXmtlWgt70%253D&md5=c45c17c74ce4c1da86e61d7698dbb330Design, Synthesis, X-ray Analysis, and Dopamine Receptor-Modulating Activity of Mimics of the "C5" Hydrogen-Bonded Conformation in the Peptidomimetic 2-Oxo-3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-1-pyrrolidineacetamideBaures, Paul W.; Ojala, William H.; Gleason, William B.; Mishra, Ram K.; Johnson, Rodney L.Journal of Medicinal Chemistry (1994), 37 (22), 3677-83CODEN: JMCMAR; ISSN:0022-2623.Analogs I and II (R = NH2) were designed and prepd. as mimics of the "C5" hydrogen-bonded structure found in the crystal structure of the title compd (III). Both compds. effectively restrict the ψ1 torsional angle to very near the value found in the x-ray structure of III, as seen in the x-ray crystallog. detn. of I ester analog II (R = OMe). I and II (R = NH2) were tested for their ability to enhance the binding of the dopamine D2 receptor agonist N-propylnorapomorphine (NPA) in the absence and presence of 5'-guanylylimidodiphosphate (Gpp(NH)p). Both compds. enhanced [3H]NPA binding in a dose-dependent manner by increasing both the binding affinity of the agonist and the no. of high-affinity sites available for binding. Both I and II (R = NH2) also attenuated the Gpp(NH)p-induced conversion of D2 receptor high-affinity states to the low-affinity states.
- 179Yu, K. L.; Rajakumar, G.; Srivastava, L. K.; Mishra, R. K.; Johnson, R. L. Dopamine receptor modulation by conformationally constrained analogues of Pro-Leu-Gly-NH2. J. Med. Chem. 1988, 31, 1430– 1436, DOI: 10.1021/jm00402a031[ACS Full Text], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXkt1egtb8%253D&md5=4b5fb96c48f174cf60d92f4ab56aace8Dopamine receptor modulation by conformationally constrained analogs of Pro-Leu-Gly-NH2Yu, Kuo Long; Rajakumar, G.; Srivastava, Lalit K.; Mishra, Ram K.; Johnson, Rodney L.Journal of Medicinal Chemistry (1988), 31 (7), 1430-6CODEN: JMCMAR; ISSN:0022-2623.Two series of conformationally constrained analogs of Pro-Leu-Gly-NH2 (PLG) have been synthesized. In one series, the Leu-Gly-NH2 dipeptide segment of PLG was replaced with the γ-lactam residues (S)- and (R)-3-amino-2-oxopyrrolidineacetamide and the δ-lactam residue (S)-3-amino-2-oxopiperidineacetamide. The corresponding δ-lactam analogs of pyroGlu-Leu-Gly-NH2 were also synthesized. In a second series of analogs, the glycinamide residue of PLG was replaced with the 2-ketopiperazine, (S)-3-amino-2-pyrrolidone, and (S)-3-amino-2-piperidone residues. The above analogs were tested for their ability to enhance the binding of the dopamine receptor agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) to striatal dopamine receptors. Only the γ-lactam analog I possess significant activity. This analog was 10,000 times more active than PLG, under preincubation conditions. It significantly enhanced the binding of ADTN at concns. of 10-9 and 10-10 M.
- 180Mishra, R. K.; Srivastava, L. K.; Johnson, R. L. Modulation of high-affinity CNS dopamine D2 receptor by L-pro-L-leu-glycinamide (PLG) analogue 3(R)-(N-L-prolylamino)-2-oxo-1-pyrrolidineacetamide. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1990, 14, 821– 827, DOI: 10.1016/0278-5846(90)90054-K[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXkt1amu74%253D&md5=4c2d99c4e75972bc622039b76307e4ccModulation of high-affinity CNS dopamine D2 receptor by L-Pro-L-Leu-glycinamide (PLG) analog 3(R)-(N-L-prolylamino)-2-oxo-1-pyrrolidineacetamideMishra, Ram K.; Srivastava, Lalit K.; Johnson, R. L.Progress in Neuro-Psychopharmacology & Biological Psychiatry (1990), 14 (5), 821-7CODEN: PNPPD7; ISSN:0278-5846.In previous studies, one of the conformationally constrained analogs of PLG, 3(R)-(N-L-prolylamino)-2-oxo-1-pyrrolidineacetamide (PAOPA), was extremely potent in enhancing the [3H]ADTN binding when membranes were preincubated with this compd. PAOPA was without effect when directly added to assay tubes. In the present study, the effect of PAOPA was examd. on agonist binding to the high-affinity state of the dopamine D2 receptor. PAOPA was able to prevent the GTP-induced conversion of the high-affinity state of dopamine D2 receptor to the low-affinity state. Thus, PAOPA modulates the affinity states of the dopamine D2 receptor, possibly by affecting its interaction with the G-protein(s).
- 181Subasinghe, N. L.; Bontems, R. J.; McIntee, E.; Mishra, R. K.; Johnson, R. L. Bicyclic thiazolidine lactam peptidomimetics of the dopamine receptor modulating peptide Pro-Leu-Gly-NH2. J. Med. Chem. 1993, 36, 2356– 2361, DOI: 10.1021/jm00068a013[ACS Full Text], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXlvFGnuro%253D&md5=3a777e873523f6b98ac8ba31951ffc0aBicyclic thiazolidine lactam peptidomimetics of the dopamine receptor modulating peptide Pro-Leu-Gly-NH2Subasinghe, Nalin L.; Bontems, Roger J.; McIntee, Edward; Mishra, Ram K.; Johnson, Rodney L.Journal of Medicinal Chemistry (1993), 36 (16), 2356-61CODEN: JMCMAR; ISSN:0022-2623.Bicyclic thiazolidine lactam peptidomimetics (I-III) were synthesized as potential analogs of the dopamine receptor modulating peptide Pro-Leu-Gly-NH2 (PLG). I and II were designed to constrain 2, ψ2 and φ3, of the 4 torsion angles that define a β-turn to values approximating those found for a type-II β-turn, while III was designed as a compd. that could not achieve a β-turn conformation. I and II enhanced the binding of the dopamine receptor agonist ADTN to the dopamine receptor, while III was inactive. Like PLG, the dose-response curves for I and II were bell-shaped in nature with the max. effect occurring at a concn. of 1 μM. I and II were more effective than PLG in enhancing the binding of ADTN to dopamine receptors. I enhanced the binding of ADTN by almost 200%, while II enhanced the binding of ADTN by about 75%. These results provide further evidence in support of the hypothesis that the bioactive conformation of PLG is a type-II β-turn.
- 182Borthwick, A. D. 2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products. Chem. Rev. 2012, 112, 3641– 3716, DOI: 10.1021/cr200398y[ACS Full Text], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmvV2ns78%253D&md5=2c30d3c51f862e424679b65784f03aa62,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural ProductsBorthwick, Alan D.Chemical Reviews (Washington, DC, United States) (2012), 112 (7), 3641-3716CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. 2,5-Diketopiperazines [such as cyclo(Trp-Pro), cyclo(Trp-Trp) and cyclo(Pro-Pro), etc.] are cyclic dipeptides obtained by the condensation of two α-amino acids. They are not only abound in nature, but also, are often produced as degrdn. products of polypeptides, esp., in processed food and beverages. The objective of the present review is to comprehensively cover the literature from 1993 until the end of 2010 on the structure, reactions, medicinal chem., and potential therapeutic applications of 2,5-diketopiperazines, in particular natural products that exhibit biol. activity. This review focuses on the soln.-phase synthesis of 2,5-diketopiperazines from the past decade (2000-2010) and will only touch briefly on solid-phase synthesis.
- 183Verma, K.; Zang, T.; Penning, T. M.; Trippier, P. C. Potent and highly selective aldo-keto reductase 1C3 (AKR1C3) inhibitors act as chemotherapeutic potentiators in acute myeloid leukemia and T-Cell acute lymphoblastic leukemia. J. Med. Chem. 2019, 62, 3590– 3616, DOI: 10.1021/acs.jmedchem.9b00090[ACS Full Text], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkt1Wgtrw%253D&md5=7142848109b6a6f7197549fd07e3057bPotent and Highly Selective Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors Act as Chemotherapeutic Potentiators in Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic LeukemiaVerma, Kshitij; Zang, Tianzhu; Penning, Trevor M.; Trippier, Paul C.Journal of Medicinal Chemistry (2019), 62 (7), 3590-3616CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Aldo-keto reductase 1C3 (AKR1C3) catalyzes the synthesis of 9α,11β-prostaglandin (PG) F2α and PGF2α prostanoids that sustain the growth of myeloid precursors in the bone marrow. The enzyme is overexpressed in acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL). Moreover, AKR1C3 confers chemotherapeutic resistance to the anthracyclines; first-line agents for the treatment of leukemias. The highly homologous isoforms AKR1C1 and AKR1C2 inactive 5α-dihydroprogesterone and their inhibition would be undesirable. We report herein, the identification of AKR1C3 inhibitors that demonstrate exquisite isoform selectivity for AKR1C3 over the other closely related isoforms to the order of >2800-fold. Biol. evaluation of our isoform selective inhibitors revealed a high degree of synergistic drug action in combination with the clin. leukemia therapeutics daunorubicin and cytarabine in in vitro cellular models of AML and primary patient-derived T-ALL cells. Our developed compds. exhibited >100-fold dose redn. index that results in complete resensitization of a daunorubicin-resistant AML cell line to the chemotherapeutic and >100-fold dose redn. of cytarabine in both AML cell lines and primary T-ALL cells.
- 184de la Fuente Revenga, M.; Fernandez-Saez, N.; Herrera-Arozamena, C.; Morales-Garcia, J. A.; Alonso-Gil, S.; Perez-Castillo, A.; Caignard, D. H.; Rivara, S.; Rodriguez-Franco, M. I. Novel N-acetyl bioisosteres of melatonin: melatonergic receptor pharmacology, physicochemical studies, and phenotypic assessment of their neurogenic potential. J. Med. Chem. 2015, 58, 4998– 5014, DOI: 10.1021/acs.jmedchem.5b00245[ACS Full Text], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptFajsL0%253D&md5=0866e59c6e177e9e2a89660f5a4c6cddNovel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potentialde la Fuente Revenga, Mario; Fernandez-Saez, Nerea; Herrera-Arozamena, Clara; Morales-Garcia, Jose A.; Alonso-Gil, Sandra; Perez-Castillo, Ana; Caignard, Daniel-Henri; Rivara, Silvia; Rodriguez-Franco, Maria IsabelJournal of Medicinal Chemistry (2015), 58 (12), 4998-5014CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Herein the authors present a new family of melatonin-based compds., in which the acetamido group of melatonin has been bioisosterically replaced by a series of reversed amides and azoles, such as oxazole, 1,2,4-oxadiazole, and 1,3,4-oxadiazole, as well as other related five-membered heterocycles, namely, 1,3,4-oxadiazol(thio)ones, 1,3,4-triazol(thio)ones, and an 1,3,4-thiadiazole. New compds. were fully characterized at melatonin receptors (MT1R and MT2R), and results were rationalized by superimposition studies of their structures to the bioactive conformation of melatonin. The authors also found that several of these melatonin-based compds. promoted differentiation of rat neural stem cells to a neuronal phenotype in vitro, in some cases to a higher extent than melatonin. This unique profile constitutes the starting point for further pharmacol. studies to assess the mechanistic pathways and the relevance of neurogenesis induced by melatonin-related structures.
- 185Byrns, M. C.; Penning, T. M. Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogs. Chem.-Biol. Interact. 2009, 178, 221– 227, DOI: 10.1016/j.cbi.2008.10.024[Crossref], [PubMed], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFOjtb0%253D&md5=67a4ebbb87d66f87b96e8b85cfd06a08Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): Role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogsByrns, Michael C.; Penning, Trevor M.Chemico-Biological Interactions (2009), 178 (1-3), 221-227CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)Aldo-keto reductase (AKR) 1C3 catalyzes the NADPH-dependent redn. of Δ4-androstene-3,17-dione to yield testosterone, redn. of estrone to yield 17β-estradiol and redn. of progesterone to yield 20α-hydroxyprogesterone. In addn., it functions as a prostaglandin (PG) F synthase and reduces PGH2 to PGF2α and PGD2 to 11β-PGF2. Immunohistochem. showed that AKR1C3 is over-expressed in invasive ductal carcinoma of the breast. Retroviral expression of AKR1C3 in MCF-7 breast carcinoma cells shows that each of the assigned reactions occur in a breast cell microenvironment. Steroid and prostaglandin conversions were monitored by radiochromatog. Prostaglandin conversion was validated by a 2nd method using HPLC coupled to APCI-MRM/MS. The combined effect of the AKR1C3 catalyzed 17- and 20-ketosteroid redns. will be to increase the 17β-estradiol:progesterone ratio in the breast. In addn., formation of PGF2 epimers would activate F prostanoid receptors and deprive PPARγ of its putative anti-proliferative PGJ2 ligands. Thus, AKR1C3 is a source of proliferative signals and a potential therapeutic target for hormone-dependent and -independent breast cancer. Two strategies for AKR1C3 inhibition based on non-steroidal anti-inflammatory drugs were developed. The 1st strategy uses the Ullmann coupling reaction to generate N-phenylanthranilate derivs. that inhibit AKR1C enzymes without affecting PGH2 synthase (PGHS) 1 or PGHS-2. The second strategy exploits the selective inhibition of AKR1C3 by indomethacin, which did not inhibit highly related AKR1C1 or AKR1C2. Using known structure-activity relationships for the inhibition of PGHS-1 and PGHS-2 by indole acetic acids we obtained N-(4-chlorobenzoyl)-melatonin as a specific AKR1C3 inhibitor (K I = 6.0 μM) that does not inhibit PGHS-1, PGHS-2, AKR1C1, or AKR1C2. Both strategies are informed by crystal structures of ternary AKR1C3·NADP+·NSAID complexes. The identification of NSAID analogs as specific inhibitors of AKR1C3 will help validate its role in the proliferation of breast cancer cells.
- 186Ji, Q.; Chang, L.; Stanczyk, F. Z.; Ookhtens, M.; Sherrod, A.; Stolz, A. Impaired dihydrotestosterone catabolism in human prostate cancer: critical role of AKR1C2 as a pre-receptor regulator of androgen receptor signaling. Cancer Res. 2007, 67, 1361– 1369, DOI: 10.1158/0008-5472.CAN-06-1593[Crossref], [PubMed], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1ynt7w%253D&md5=5a85f84c8edadd0b3e10dc913484652fImpaired Dihydrotestosterone Catabolism in Human Prostate Cancer: Critical Role of AKR1C2 as a Pre-Receptor Regulator of Androgen Receptor SignalingJi, Qing; Chang, Lilly; Stanczyk, Frank Z.; Ookhtens, Murad; Sherrod, Andy; Stolz, AndrewCancer Research (2007), 67 (3), 1361-1369CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)We previously reported the selective loss of AKR1C2 and AKR1C1 in prostate cancers compared with their expression in paired benign tissues. We now report that dihydrotestosterone (DHT) levels are significantly greater in prostate cancer tumors compared with their paired benign tissues. Decreased catabolism seems to account for the increased DHT levels as expression of AKR1C2 and SRD5A2 was reduced in these tumors compared with their paired benign tissues. After 4 h of incubation with benign tissue samples, 3H-DHT was predominately catabolized to the 5α-androstane-3α,17beta-diol metabolite. Reduced capacity to metabolize DHT was obsd. in tumor samples from four of five freshly isolated pairs of tissue samples, which paralleled loss of AKR1C2 and AKR1C1 expression. LAPC-4 cells transiently transfected with AKR1C1 and AKR1C2, but not AKR1C3, were able to significantly inhibit a dose-dependent, DHT-stimulated proliferation, which was assocd. with a significant redn. in the concn. of DHT remaining in the media. R1881-stimulated proliferation was equiv. in all transfected cells, showing that metab. of DHT was responsible for the inhibition of proliferation. PC-3 cells overexpressing AKR1C2 and, to a lesser extent, AKR1C1 were able to significantly inhibit DHT-dependent androgen receptor reporter activity, which was abrogated by increasing DHT levels. We speculate that selective loss of AKR1C2 in prostate cancer promotes clonal expansion of tumor cells by enhancement of androgen-dependent cellular proliferation by reducing DHT metab.
- 187Penning, T. M.; Bauman, D. R.; Jin, Y.; Rizner, T. L. Identification of the molecular switch that regulates access of 5α-DHT to the androgen receptor. Mol. Cell. Endocrinol. 2007, 265–266, 77– 82, DOI: 10.1016/j.mce.2006.12.007[Crossref], [PubMed], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXit12msb0%253D&md5=2ff342e0a26d247c4e901431f0f8ba2bIdentification of the molecular switch that regulates access of 5α-DHT to the androgen receptorPenning, Trevor M.; Bauman, David R.; Jin, Yi; Rizner, Tea LanisikMolecular and Cellular Endocrinology (2007), 265-266 (), 77-82CODEN: MCEND6; ISSN:0303-7207. (Elsevier Ltd.)A review. Pairs of hydroxysteroid dehydrogenases (HSDs) govern ligand access to steroid receptors in target tissues and act as mol. switches. By acting as reductases or oxidases, HSDs convert potent ligands into their cognate inactive metabolites or vice versa. This pre-receptor regulation of steroid hormone action may have profound effects on hormonal response. We have identified the HSDs responsible for regulating ligand access to the androgen receptor (AR) in human prostate. Type 3 3α-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) acts solely as a reductase to convert 5α-dihydrotestosterone (DHT), a potent ligand for the AR (Kd=10-11 M for the AR), to the inactive androgen 3α-androstanediol (Kd=10-6 M for the AR); while RoDH like 3α-HSD (a short-chain dehydrogenase/reductase (SDR)) acts solely as an oxidase to convert 3α-androstanediol back to 5α-DHT. Our studies suggest that aldo-keto reductase (AKRs) and SDRs function as reductases and oxidases, resp., to control ligand access to nuclear receptors.
- 188Yin, Y. D.; Fu, M.; Brooke, D. G.; Heinrich, D. M.; Denny, W. A.; Jamieson, S. M. The activity of SN33638, an inhibitor of AKR1C3, on testosterone and 17β-estradiol production and function in castration-resistant prostate cancer and ER-positive breast cancer. Front. Oncol. 2014, 4, 159, DOI: 10.3389/fonc.2014.00159[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfptVKksw%253D%253D&md5=ef337064d6f2a20aa22ac29867ff6b13The Activity of SN33638, an Inhibitor of AKR1C3, on Testosterone and 17β-Estradiol Production and Function in Castration-Resistant Prostate Cancer and ER-Positive Breast CancerYin Yarong Diana; Fu Melissa; Brooke Darby G; Heinrich Daniel M; Denny William A; Jamieson Stephen M FFrontiers in oncology (2014), 4 (), 159 ISSN:2234-943X.AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC) and estrogen receptor (ER)-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression. A panel of CRPC, ER-positive breast cancer and high/low AKR1C3-expressing cell lines were treated with SN33638, a selective inhibitor of AKR1C3, in the presence of hormone or prostaglandin (PG) precursors, prior to evaluation of cell proliferation and levels of 11β-PG F2α (11β-PGF2α), testosterone, 17β-estradiol, and prostate-specific antigen (PSA). A meta-analysis of AKR1C3 mRNA expression in patient samples was also conducted, which revealed that AKR1C3 mRNA was upregulated in CRPC, but downregulated in ER-positive breast cancer. 11β-PGF2α and testosterone levels in the cell line panel correlated with AKR1C3 protein expression. SN33638 prevented 11β-PGF2α formation in cell lines that expressed AKR1C3, but partially inhibited testosterone formation and subsequently cell proliferation and/or PSA expression only in high (LAPC4 AKR1C3-overexpressing cells) or moderate (22RV1) AKR1C3-expressing cell lines. SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines. Although SN33638 could prevent 11β-PGF2α formation, its ability to prevent testosterone and 17β-estradiol production and their roles in CRPC and ER-positive breast cancer progression was limited due to AKR1C3-independent steroid hormone production, except in LAPC4 AKR1C3 cells where the majority of testosterone was AKR1C3-dependent. These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required for their growth.
- 189Loriot, Y.; Fizazi, K.; Jones, R. J.; Van den Brande, J.; Molife, R. L.; Omlin, A.; James, N. D.; Baskin-Bey, E.; Heeringa, M.; Baron, B.; Holtkamp, G. M.; Ouatas, T.; De Bono, J. S. Safety, tolerability and anti-tumour activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer: multi-centre phase I/II study. Invest. New Drugs 2014, 32, 995– 1004, DOI: 10.1007/s10637-014-0101-x[Crossref], [PubMed], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXntlejs7g%253D&md5=58d51588f7b4984b516a4c4a410189e3Safety, tolerability and anti-tumor activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer: multi-centre phase I/II studyLoriot, Yohann; Fizazi, Karim; Jones, Robert J.; Van den Brande, Jan; Molife, Rhoda L.; Omlin, Aurelius; James, Nicholas D.; Baskin-Bey, Edwina; Heeringa, Marten; Baron, Benoit; Holtkamp, Gertjan M.; Ouatas, Taoufik; De Bono, Johann S.Investigational New Drugs (2014), 32 (5), 995-1004CODEN: INNDDK; ISSN:0167-6997. (Springer)Background: ASP9521 is a first-in-class orally available inhibitor of the enzyme 17 β-hydroxysteroid dehydrogenase type 5 (17 βHSD5; AKR1C3), catalyzing the conversion of dehydroepiandrosterone and androstenedione into 5-androstenediol and testosterone. It has demonstrated anti-tumor activity in in vitro and in vivo preclin. models. Material and methods: This first-in-man phase I/II study utilized a 3 + 3 dose escalation design starting at 30 mg ASP9521/day, with the aim of defining a max. tolerated dose, as defined by the incidence of dose-limiting toxicities. Eligible patients received ASP9521 orally for 12 wk. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics and anti-tumor activity were assessed. Results: Thirteen patients (median age: 68 years; range 52-76) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy were included; 12 patients discontinued treatment at or before week 13, mainly due to disease progression. The most common adverse events were grade 1/2 and included asthenia (N = 5), constipation (N = 4), diarrhoea (N = 3), back pain (N = 3) and cancer pain (N = 3). PK demonstrated a half-life (t1/2) ranging from 16 to 35 h, rapid absorption and dose proportionality. No biochem. or radiol. responses were identified; neither endocrine biomarker levels nor circulating tumor cell counts were altered by ASP9521. Given the lack of observable clin. activity, the study was terminated without implementing a planned 12-wk dose expansion part at selected doses or a planned food-effect study part. Conclusions: In patients with mCRPC, ASP9521 demonstrated dose-proportional increase in exposure over the doses evaluated, with an acceptable safety and tolerability profile. However, the novel androgen biosynthesis inhibitor showed no relevant evidence of clin. activity.
- 190Kikuchi, A.; Furutani, T.; Azami, H.; Watanabe, K.; Niimi, T.; Kamiyama, Y.; Kuromitsu, S.; Baskin-Bey, E.; Heeringa, M.; Ouatas, T.; Enjo, K. In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3). Invest. New Drugs 2014, 32, 860– 870, DOI: 10.1007/s10637-014-0130-5[Crossref], [PubMed], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFWisrfL&md5=2aeb865497f4e85ba52d7556da8fab22In vitro and in vivo characterisation of ASP9521: a novel, selective, orally bioavailable inhibitor of 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5; AKR1C3)Kikuchi, Aya; Furutani, Takashi; Azami, Hidenori; Watanabe, Kazushi; Niimi, Tatsuya; Kamiyama, Yoshiteru; Kuromitsu, Sadao; Baskin-Bey, Edwina; Heeringa, Marten; Ouatas, Taoufik; Enjo, KentaroInvestigational New Drugs (2014), 32 (5), 860-870CODEN: INNDDK; ISSN:0167-6997. (Springer)Background Aldo-keto reductase 1C3 [AKR1C3;17β-hydroxysteroid dehydrogenase type 5 (17βHSD5)], plays a crucial role in persistent prodn. of androgens despite castration, by catalyzing conversion of the adrenal androgens dehydroepiandrosterone and androstenedione (AD) into androstenediol and testosterone (T). Hence, AKR1C3 is a promising therapeutic target in castration-resistant prostate cancer, as combination of an AKR1C3 inhibitor and a gonadotropin-releasing hormone analog may lead to complete androgen blockade. This study describes the preclin. characterization of the novel AKR1C3 inhibitor ASP9521. Methods The inhibitory effect of ASP9521 on AKR1C3-mediated conversion from AD into T was evaluated both in vitro and in vivo, using CWR22R xenografted mice. The effect of ASP9521 on PSA prodn. and cell proliferation was tested using LNCaP cells stably expressing human AKR1C3 (LNCaP-AKR1C3). Pharmacokinetics of ASP9521 were studied in rats, dogs and cynomolgus monkeys. Results ASP9521 inhibited conversion of AD into T by recombinant human or cynomolgus monkey AKR1C3 in a concn.-dependent manner (IC50,human: 11 nmol/L; IC50,monkey: 49 nmol/L). ASP9521 showed >100-fold selectivity for AKR1C3 over the isoform AKR1C2. In LNCaP-AKR1C3 cells, ASP9521 suppressed AD-dependent PSA prodn. and cell proliferation. In CWR22R xenografts, single oral administration of ASP9521 (3 mg/kg) inhibited AD-induced intratumoral T prodn. and this inhibitory effect was maintained for 24 h. After oral administration, ASP9521 was rapidly eliminated from plasma, while its intratumoral concn. remained high. The bioavailability of ASP9521 after oral administration (1 mg/kg) was 35 %, 78 % and 58 % in rats, dogs and monkeys, resp. Conclusions ASP9521 is a potent, selective, orally bioavailable AKR1C3 inhibitor.
- 191Endo, S.; Matsunaga, T.; Kanamori, A.; Otsuji, Y.; Nagai, H.; Sundaram, K.; El-Kabbani, O.; Toyooka, N.; Ohta, S.; Hara, A. Selective inhibition of human type-5 17β-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis. J. Nat. Prod. 2012, 75, 716– 721, DOI: 10.1021/np201002x[ACS Full Text], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlsFKlt7g%253D&md5=d3b7ad46dceac38f43b372284336f1dcSelective Inhibition of Human Type-5 17β-Hydroxysteroid Dehydrogenase (AKR1C3) by Baccharin, a Component of Brazilian PropolisEndo, Satoshi; Matsunaga, Toshiyuki; Kanamori, Ayano; Otsuji, Yoko; Nagai, Hiroko; Sundaram, Krithika; El-Kabbani, Ossama; Toyooka, Naoki; Ohta, Shozo; Hara, AkiraJournal of Natural Products (2012), 75 (4), 716-721CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)The human aldo-keto reductase (AKR) 1C3, also known as type-5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase, has been suggested as a therapeutic target in the treatment of prostate and breast cancers. In this study, AKR1C3 inhibition was examd. by Brazilian propolis-derived cinnamic acid derivs. that show potential antitumor activity, and baccharin is a potent competitive inhibitor (Ki 56 nM) with high selectivity, showing no significant inhibition toward other AKR1C isoforms (AKR1C1, AKR1C2, and AKR1C4). Mol. docking and site-directed mutagenesis studies suggested that the nonconserved residues Ser 118, Met 120, and Phe 311 in AKR1C3 are important for detg. the inhibitory potency and selectivity of baccharin. The AKR1C3-mediated metab. of 17-ketosteroid and farnesal in cancer cells was inhibited by baccharin, which was effective from 0.2 μM with an IC50 value of about 30 μM. Addnl., baccharin suppressed the proliferation of PC3 prostatic cancer cells stimulated by AKR1C3 overexpression. This study is the first demonstration that baccharin is a highly selective inhibitor of AKR1C3.
- 192Zang, T.; Verma, K.; Chen, M.; Jin, Y.; Trippier, P. C.; Penning, T. M. Screening baccharin analogs as selective inhibitors against type 5 17β-hydroxysteroid dehydrogenase (AKR1C3). Chem.-Biol. Interact. 2015, 234, 339– 348, DOI: 10.1016/j.cbi.2014.12.015[Crossref], [PubMed], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXkslejsw%253D%253D&md5=13166382f86d745545f3c5dc55077cd8Screening baccharin analogs as selective inhibitors against type 5 17β-hydroxysteroid dehydrogenase (AKR1C3)Zang, Tianzhu; Verma, Kshitij; Chen, Mo; Jin, Yi; Trippier, Paul C.; Penning, Trevor M.Chemico-Biological Interactions (2015), 234 (), 339-348CODEN: CBINA8; ISSN:0009-2797. (Elsevier Ireland Ltd.)Aldo-keto reductase 1C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase, is a downstream steroidogenic enzyme and converts androgen precursors to the potent androgen receptor ligands: testosterone and 5α-dihydrotestosterone. Studies have shown that AKR1C3 is involved in the development of castration resistant prostate cancer (CRPC) and that it is a rational drug target for the treatment of CRPC. Baccharin, a component of Brazilian propolis, has been obsd. to exhibit a high inhibitory potency and selectivity for AKR1C3 over other AKR1C isoforms and is a promising lead compd. for developing more potent and selective inhibitors. Here, we report the screening of fifteen baccharin analogs as selective inhibitors against AKR1C3 vs. AKR1C2 (type 3 3α-hydroxysteroid dehydrogenase). Among these analogs, the inhibitory activity and selectivity of thirteen compds. were evaluated for the first time. The substitution of the 4-dihydrocinnamoyloxy group of baccharin by an acetate group displayed nanomolar inhibitory potency (IC50: 440 nM) and a 102-fold selectivity over AKR1C2. By contrast, when the cinnamic acid group of baccharin was esterified, there was a dramatic decrease in potency and selectivity for AKR1C3 in comparison to baccharin. Low or sub-micromolar inhibition was obsd. when the 3-prenyl group of baccharin was removed, and the selectivity over AKR1C2 was low. Although unsubstituted baccharin was still the most potent (IC50: 100 nM) and selective inhibitor for AKR1C3, these data provide structure-activity relationships required for the optimization of new baccharin analogs. They suggest that the carboxylate group on cinnamic acid, the prenyl group, and either retention of 4-dihydrocinnamoyloxy group or acetate substituent on cinnamic acid are important to maintain the high potency and selectivity for AKR1C3.
- 193Verma, K.; Zang, T.; Gupta, N.; Penning, T. M.; Trippier, P. C. Selective AKR1C3 inhibitors potentiate chemotherapeutic activity in multiple acute myeloid leukemia (AML) cell lines. ACS Med. Chem. Lett. 2016, 7, 774– 779, DOI: 10.1021/acsmedchemlett.6b00163[ACS Full Text], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVektrfI&md5=433b508f945e347873b1a72f1941af30Selective AKR1C3 Inhibitors Potentiate Chemotherapeutic Activity in Multiple Acute Myeloid Leukemia (AML) Cell LinesVerma, Kshitij; Zang, Tianzhu; Gupta, Nehal; Penning, Trevor M.; Trippier, Paul C.ACS Medicinal Chemistry Letters (2016), 7 (8), 774-779CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We report the design, synthesis, and evaluation of potent and selective inhibitors of aldo-keto reductase 1C3 (AKR1C3), an important enzyme in the regulatory pathway controlling proliferation, differentiation, and apoptosis in myeloid cells. Combination treatment with the nontoxic AKR1C3 inhibitors and etoposide or daunorubicin in acute myeloid leukemia cell lines, elicits a potent adjuvant effect, potentiating the cytotoxicity of etoposide by up to 6.25-fold and the cytotoxicity of daunorubicin by >10-fold. The results validate AKR1C3 inhibition as a common adjuvant target across multiple AML subtypes. These compds. in coadministration with chemotherapeutics in clin. use enhance therapeutic index and may avail chemotherapy as a treatment option to the pediatric and geriatric population currently unable to tolerate the side effects of cancer drug regimens.
- 194Pandi-Perumal, S. R.; Srinivasan, V.; Maestroni, G. J. M.; Cardinali, D. P.; Poeggeler, B.; Hardeland, R. Melatonin: nature’s most versatile biological signal?. FEBS J. 2006, 273, 2813– 2838, DOI: 10.1111/j.1742-4658.2006.05322.x[Crossref], [PubMed], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XnvFaisr4%253D&md5=964603edf0a241876aeb516cbf610159Melatonin. Nature's most versatile biological signal?Pandi-Perumal, S. R.; Srinivasan, V.; Maestroni, G. J. M.; Cardinali, D. P.; Poeggeler, B.; Hardeland, R.FEBS Journal (2006), 273 (13), 2813-2838CODEN: FJEOAC; ISSN:1742-464X. (Blackwell Publishing Ltd.)A review. Melatonin is a ubiquitous mol. and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a no. of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronol. pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiol. functions through paracrine signaling. Melatonin has also been extd. from the seeds and leaves of a no. of plants and its concn. in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiol. functions. In addn. to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong anti-apoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic mol.' in seasonal reprodn. has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiol. functions.
- 195Jockers, R.; Maurice, P.; Boutin, J. A.; Delagrange, P. Melatonin receptors, heterodimerization, signal transduction and binding sites: what’s new?. Br. J. Pharmacol. 2008, 154, 1182– 1195, DOI: 10.1038/bjp.2008.184[Crossref], [PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosVCjtLk%253D&md5=285de0da9971c744d5620dc33aa92e97Melatonin receptors, heterodimerization, signal transduction and binding sites: what's new?Jockers, R.; Maurice, P.; Boutin, J. A.; Delagrange, P.British Journal of Pharmacology (2008), 154 (6), 1182-1195CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)A review. Melatonin is a neurohormone that has been claimed to be involved in a wide range of physiol. functions. Nevertheless, for most of its effects, the mechanism of action is not really known. In mammals, two melatonin receptors, MT1 and MT2, have been cloned. They belong to the G-protein-coupled receptor (GPCR) superfamily. They share some specific short amino-acid sequences, which suggest that they represent a specific subfamily. Another receptor from the same subfamily, the melatonin-related receptor has been cloned in different species including humans. This orphan receptor also named GPR50 does not bind melatonin and its endogenous ligand is still unknown. Nevertheless, this receptor has been shown to behave as an antagonist of the MT1 receptor, which opens new pharmacol. perspectives for GPR50 despite the lack of endogenous or synthetic ligands. Moreover, MT1 and MT2 interact together through the formation of heterodimers at least in cells transfected with the cDNA of these two receptors. Lastly, signaling complexes assocd. with MT1 and MT2 receptors are starting to be deciphered. A third melatonin-binding site has been purified and characterized as the enzyme quinone reductase 2 (QR2). Inhibition of QR2 by melatonin may explain melatonin's protective effect that has been reported in different animal models and that is generally assocd. with its well-documented antioxidant properties.
- 196Li, Y.; Li, S.; Zhou, Y.; Meng, X.; Zhang, J. J.; Xu, D. P.; Li, H. B. Melatonin for the prevention and treatment of cancer. Oncotarget 2017, 8, 39896– 39921, DOI: 10.18632/oncotarget.16379[Crossref], [PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cvosVGmtw%253D%253D&md5=afda46503108e4e492f7d50a56ad98f4Melatonin for the prevention and treatment of cancerLi Ya; Zhou Yue; Meng Xiao; Zhang Jiao-Jiao; Xu Dong-Ping; Li Hua-Bin; Li Sha; Li Hua-BinOncotarget (2017), 8 (24), 39896-39921 ISSN:.The epidemiological studies have indicated a possible oncostatic property of melatonin on different types of tumors. Besides, experimental studies have documented that melatonin could exert growth inhibition on some human tumor cells in vitro and in animal models. The underlying mechanisms include antioxidant activity, modulation of melatonin receptors MT1 and MT2, stimulation of apoptosis, regulation of pro-survival signaling and tumor metabolism, inhibition on angiogenesis, metastasis, and induction of epigenetic alteration. Melatonin could also be utilized as adjuvant of cancer therapies, through reinforcing the therapeutic effects and reducing the side effects of chemotherapies or radiation. Melatonin could be an excellent candidate for the prevention and treatment of several cancers, such as breast cancer, prostate cancer, gastric cancer and colorectal cancer. This review summarized the anticancer efficacy of melatonin, based on the results of epidemiological,experimental and clinical studies, and special attention was paid to the mechanisms of action.
- 197Alghamdi, B. S. The neuroprotective role of melatonin in neurological disorders. J. Neurosci. Res. 2018, 96, 1136– 1149, DOI: 10.1002/jnr.24220[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjs1amt7w%253D&md5=58edf0fc7b3b82a725505261df9eb56fThe neuroprotective role of melatonin in neurological disordersAlghamdi, B. S.Journal of Neuroscience Research (2018), 96 (7), 1136-1149CODEN: JNREDK; ISSN:0360-4012. (Wiley-Blackwell)A review. Melatonin is a neurohormone secreted from the pineal gland and has a wide-ranging regulatory and neuroprotective role. It has been reported that melatonin level is disturbed in some neurol. conditions such as stroke, Alzheimer's disease, and Parkinson's disease, which indicates its involvement in the pathophysiol. of these diseases. Its properties qualify it to be a promising potential therapeutic neuroprotective agent, with no side effects, for some neurol. disorders. This review discusses and localizes the effect of melatonin in the pathophysiol. of some diseases.
- 198Karamitri, A.; Jockers, R. Melatonin in type 2 diabetes mellitus and obesity. Nat. Rev. Endocrinol. 2019, 15, 105– 125, DOI: 10.1038/s41574-018-0130-1[Crossref], [PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFWrtLbE&md5=5782714fe2669b78fe02e75089cd9e95Melatonin in type 2 diabetes mellitus and obesityKaramitri, Angeliki; Jockers, RalfNature Reviews Endocrinology (2019), 15 (2), 105-125CODEN: NREABD; ISSN:1759-5029. (Nature Research)A review. Despite considerable advances in the past few years, obesity and type 2 diabetes mellitus (T2DM) remain two major challenges for public health systems globally. In the past 9 years, genome-wide assocn. studies (GWAS) have established a major role for genetic variation within the MTNR1B locus in regulating fasting plasma levels of glucose and in affecting the risk of T2DM. This discovery generated a major interest in the melatonergic system, in particular the melatonin MT2 receptor (which is encoded by MTNR1B). In this Review, we discuss the effect of melatonin and its receptors on glucose homeostasis, obesity and T2DM. Preclin. and clin. post-GWAS evidence of frequent and rare variants of the MTNR1B locus confirmed its importance in regulating glucose homeostasis and T2DM risk with minor effects on obesity. However, these studies did not solve the question of whether melatonin is beneficial or detrimental, an issue that will be discussed in the context of the peculiarities of the melatonergic system. Melatonin receptors might have therapeutic potential as they belong to the highly druggable G protein-coupled receptor superfamily. Clarifying the precise role of melatonin and its receptors on glucose homeostasis is urgent, as melatonin is widely used for other indications, either as a prescribed medication or as a supplement without medical prescription, in many countries in Europe and in the USA.
- 199Leclerc, V.; Fourmaintraux, E.; Depreux, P.; Lesieur, D.; Morgan, P.; Howell, H. E.; Renard, P.; Caignard, D. H.; Pfeiffer, B.; Delagrange, P.; Guardiola-Lemaitre, B.; Andrieux, J. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. Bioorg. Med. Chem. 1998, 6, 1875– 1887, DOI: 10.1016/S0968-0896(98)00147-3[Crossref], [PubMed], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXntlOhtbs%253D&md5=6ed68fd9dbf928caa550601c70cb3200Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligandsLeclerc, Veronique; Fourmaintraux, Eric; Depreux, Patrick; Lesieur, Daniel; Morgan, Peter; Howell, H. Edward; Renard, Pierre; Caignard, Daniel-Henri; Pfeiffer, Bruno; Delagrange, Philippe; Guardiola-Lemaitre, Beatrice; Andrieux, JeanBioorganic & Medicinal Chemistry (1998), 6 (10), 1875-1887CODEN: BMECEP; ISSN:0968-0896. (Elsevier Science Ltd.)A previous paper reported the synthesis of melatonin receptor ligands. In order to complete the structure-activity relationships and to obtain antagonists to the melatonin receptor, a new series of naphthalenic analogs of melatonin have been synthesized. Modifications include deletion of the 7-methoxy group, replacement of the ethylene moiety, replacement of the amidic function by bioisosteres, and replacement of the naphthalenic nucleus by other bicyclic rings. Almost all the structural modifications lead to decreased affinity for the melatonin receptor. However, the N-n-Pr urea deriv. is a very potent ligand at this receptor (pKi = 14.3). Most interestingly deletion of the methoxy group resulted in the first antagonist in this series. This mol., a Pr deriv., or N-[2-(1-naphthyl)-ethyl]cyclobutyl carboxamide has been selected for preclin. development.
- 200Morgan, P. J.; Williams, L. M.; Davidson, G.; Lawson, W.; Howell, E. Melatonin receptors on ovine pars tuberalis: characterization and autoradiographicai localization. J. Neuroendocrinol. 1989, 1, 1– 4, DOI: 10.1111/j.1365-2826.1989.tb00068.x[Crossref], [PubMed], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXhs1Gmuw%253D%253D&md5=a5d805b08a2d01a3bd1579750b9fd469Melatonin receptors on ovine pars tuberalis: characterization and autoradiographical localizationMorgan, Peter J.; Williams, Lynda M.; Davidson, Gary; Lawson, Wilfred; Howell, EdwardJournal of Neuroendocrinology (1989), 1 (1), 1-4CODEN: JOUNE2; ISSN:0953-8194.The highly specific ligand [125I]melatonin was used to demonstrate that it binds exclusively, with very high affinity, to the pars tuberalis but not the pars distalis of the adult sheep adenohypophysis. Evidently, the PT has a distinct role in relation to melatonin action and seasonal reprodn.
- 201He, P.; Ouyang, X.; Zhou, S.; Yin, W.; Tang, C.; Laudon, M.; Tian, S. A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer’ disease. Horm. Behav. 2013, 64, 1– 7, DOI: 10.1016/j.yhbeh.2013.04.009[Crossref], [PubMed], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVOjsb%252FO&md5=606e93bc9b1833602139c79e501b1b23A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer' diseaseHe, Pingping; Ouyang, Xinping; Zhou, Shouhong; Yin, Weidong; Tang, Chaoke; Laudon, Moshe; Tian, ShaowenHormones and Behavior (2013), 64 (1), 1-7CODEN: HOBEAO; ISSN:0018-506X. (Elsevier Inc.)Previous studies have shown that melatonin is implicated in modulating learning and memory processing. Melatonin also exerts neuroprotective activities against Aβ-induced injury in vitro and in vivo. Neu-P11 (piromelatine, N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2-carboxamide) is a novel melatonin (MT1/MT2) receptor agonist and a serotonin 5-HT1A/1D receptor agonist recently developed for the treatment of insomnia. In the present study we firstly investigated whether Neu-P11 and melatonin enhance memory performance in the novel object recognition (NOR) task in rats, and then assessed whether Neu-P11 and melatonin improve neuronal and cognitive impairment in a rat model of Alzheimer' disease (AD) induced by intrahippocampal Aβ(1-42) injection. The results showed that a single morning or afternoon administration of Neu-P11 enhanced object recognition memory measured at 4 or 24 h after training. Melatonin was effective in the memory facilitating effects only when administered in the afternoon. Further results showed that intrahippocampal Aβ(1-42) injection resulted in hippocampal cellular loss, as well as decreased learning ability and memory in the Y maze and NOR tasks in rats. Neu-P11 but not melatonin attenuated cellular loss and cognitive impairment in the rat AD model. The current data suggest that Neu-P11 may serve as a novel agent for the treatment of AD.
- 202Tian, S. W.; Laudon, M.; Han, L.; Gao, J.; Huang, F. L.; Yang, Y. F.; Deng, H. F. Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent models. Acta Pharmacol. Sin. 2010, 31, 775– 783, DOI: 10.1038/aps.2010.80[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXotlSntbc%253D&md5=0e967edd638bb89b6bd19e51d771ac49Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent modelsTian, Shao-wen; Laudon, Moshe; Han, Li; Gao, Jun; Huang, Fu-lian; Yang, Yu-feng; Deng, Hai-fengActa Pharmacologica Sinica (2010), 31 (7), 775-783CODEN: APSCG5; ISSN:1671-4083. (Nature Publishing Group)Aim: To investigate the potential antidepressant and anxiolytic effects of Neu-P11, a novel melatonin agonist, in two models of depression in rats and a model of anxiety in mice. Methods: In the learned helplessness test (LH), Neu-P11 or melatonin (25-100 mg/kg, i.p.) was administered to rats 2 h before the beginning of the dark phase once a day for 5 days and the no. of escape failures and intertrial crossings during the test phase were recorded. In the forced swimming test (FST), rats received a single or repeated administration of Neu-P11 (25-100 mg/kg, i.p.). The total period of immobility during the test phase was assessed. In the elevated plus-maze test (EPM), mice were treated with Neu-P11 (25-100 mg/kg, i.p.) or melatonin in the morning or in the evening and tested 2 h later. The percentage of time spent in the open arms and the open arms entries were assessed. Results: In the LH test, Neu-P11 but not melatonin significantly decreased the escape deficit and had no effect on the intertrial crossings. In the FST, a single or repeated administration of Neu-P11, either in the morning or in the evening, significantly decreased the duration of immobility. In the EPM test, Neu-P11 significantly increased the percentage of time spent in the open arms and the open arms entries irresp. to the time of administration. Melatonin was effective only when administered in the afternoon. Conclusion: The results demonstrate that Neu-P11 exerts antidepressant and anxiolytic activities in rodent models.
- 203Rami, M.; Landagaray, E.; Ettaoussi, M.; Boukhalfa, K.; Caignard, D. H.; Delagrange, P.; Berthelot, P.; Yous, S. Novel conformationally constrained analogues of agomelatine as new melatoninergic ligands. Molecules 2013, 18, 154– 166, DOI: 10.3390/molecules18010154[Crossref], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpsFemsw%253D%253D&md5=3742d28bfe6f3f12b98905b07429bde7Novel conformationally constrained analogues of agomelatine as new melatoninergic ligandsRami, Marouan; Landagaray, Elodie; Ettaoussi, Mohamed; Boukhalfa, Koussayla; Caignard, Daniel-Henri; Delagrange, Philippe; Berthelot, Pascal; Yous, SaidMolecules (2013), 18 (), 154-166CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Novel conformationally restricted analogs of agomelatine were synthesized and pharmacol. evaluated at MT1-receptor ligands and MT2 melatoninergic receptor ligands. s. Replacement of the N-acetyl side chain of agomelatine by oxathiadiazole 2-oxide, oxadiazolone, tetrazole, oxazolidinone, pyrrolidinone, imidazolidinedione, thiazole, and isoxazole groups led to a decrease of the melatoninergic binding affinity, particularly at MT1. Two compds. exhibiting nanomolar affinity towards the MT2 receptors subtypes have shown the most interesting pharmacol. results of this series with the appearance of a weak MT2-selectivity. The title compds. thus formed included an imidazolidinedione analog (I) [5-[(7-methoxy-1-naphthalenyl)methyl]-2,4-imidazolidinedione] and related substances, such as a thiazole analog, isoxazole analog, oxazole analog, triazole analog.
- 204Pala, D.; Lodola, A.; Bedini, A.; Spadoni, G.; Rivara, S. Homology models of melatonin receptors: challenges and recent advances. Int. J. Mol. Sci. 2013, 14, 8093– 8121, DOI: 10.3390/ijms14048093[Crossref], [PubMed], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntlCmtbk%253D&md5=09a98e3c67eeb7bcb0119d5c91a818e5Homology models of melatonin receptors: challenges and recent advancesPala, Daniele; Lodola, Alessio; Bedini, Annalida; Spadoni, Gilberto; Rivara, SilviaInternational Journal of Molecular Sciences (2013), 14 (4), 8093-8121, 29 pp.CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a no. of different MT1 and MT2 receptor homol. models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described and they will be discussed in light of the available information from mutagenesis expts. and ligand-based pharmacophore models. The ability of these ligand-receptor complexes to rationalize structure-activity relationships of known series of melatonergic compds. will be commented upon.
- 205Jagtap, A. D.; Kondekar, N. B.; Sadani, A. A.; Chern, J. W. Ureas: applications in drug design. Curr. Med. Chem. 2017, 24, 622– 651, DOI: 10.2174/0929867323666161129124915[Crossref], [PubMed], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlsVChurg%253D&md5=a3b883c65d950d7e698b40bb71a7f938Ureas: Applications in Drug DesignJagtap, Ajit Dhananjay; Kondekar, Nagendra Bharatrao; Sadani, Amit A.; Chern, Ji-WangCurrent Medicinal Chemistry (2017), 24 (6), 622-651CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)The unique hydrogen binding capabilities of ureas make them an important functional group to make drug-target interactions and thus incorporated in small mols. displaying broad range of bioactivities. The related research and numerous excellent achievements of ureas applicability in drug design for the modulation of selectivity, stability, toxicity and pharmacokinetic profile of lead mols. have become active topic. This review aims to provide insights in to the significance of urea in drug design by summarizing successful studies of various urea derivs. as modulators biol. targets (viz. kinases, NAMPT, sol. epoxide hydrolases, mTOR, proteases, gyrB/parE, and epigenetic enzymes such as HDAC, PRMT or DOT1L etc.). The findings of this review confirm the importance of urea moiety in medicinal chem. and stimulate its use as a structural motif with rational decision making approach.
- 206Ghosh, A. K.; Brindisi, M. Urea derivatives in modern drug discovery and medicinal chemistry. J. Med. Chem. 2020, 63 (6), 2751– 2788, DOI: 10.1021/acs.jmedchem.9b01541[ACS Full Text], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1GksbrF&md5=f888b6af362248abcb16573d8cb69e6dUrea Derivatives in Modern Drug Discovery and Medicinal ChemistryGhosh, Arun K.; Brindisi, MargheritaJournal of Medicinal Chemistry (2020), 63 (6), 2751-2788CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The urea functionality is inherent to numerous bioactive compds., including a variety of clin. approved therapies. Urea-contg. compds. are increasingly used in medicinal chem. and drug design in order to establish key drug-target interactions and also to fine-tune crucial drug-like properties. In this perspective, physicochem. and conformational properties of urea derivs. are highlighted. Outlines of traditional reagents and chem. procedures for the prepn. of ureas are provided. Also, newly developed methodologies mainly aimed at overcoming safety issues assocd. with traditional synthesis are discussed. Finally, a broad overview of urea-based medicinally relevant compds., ranging from approved drugs to recent medicinal chem. developments is provided.
- 207Roark, W. H.; Roth, B. D.; Holmes, A.; Trivedi, B. K.; Kieft, K. A.; Essenburg, A. D.; Krause, B. R.; Stanfield, R. L. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 2. modification of fatty acid anilide ACAT inhibitors: bioisosteric replacement of the amide bond. J. Med. Chem. 1993, 36, 1662– 1668, DOI: 10.1021/jm00063a016[ACS Full Text], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXksV2jsbo%253D&md5=deeb4c1a41e69dcacff1fb51b3ff1e46Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 2. Modification of fatty acid anilide ACAT inhibitors: bioisosteric replacement of the amide bondRoark, W. Howard; Roth, Bruce D.; Holmes, Ann; Trivedi, Bharat K.; Kieft, Karen A.; Essenburg, Arnold D.; Krause, Brian R.; Stanfield, Richard L.Journal of Medicinal Chemistry (1993), 36 (11), 1662-8CODEN: JMCMAR; ISSN:0022-2623.In order to further define the structural features necessary for potent inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) in vitro and cholesterol lowering in vivo, a systematic study of bioisosteric replacements for the amide bond in our previously identified series of fatty acid anilide ACAT inhibitors was undertaken. In order to further define the structural features necessary for potent inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) in vitro and cholesterol lowering in vivo, a systematic study of bioisosteric replacements for the amide bond in our previously identified series of fatty acid anilide ACAT inhibitors was undertaken. Only replacement of amide bonds with isosteres having both hydrogen bond donor and acceptor functionalities yielded compds. retaining ACAT inhibitory activity. Replacement of the amide bond with the urea bioisostere yielded compds. that were potent ACAT inhibitors in vitro and efficacious hypocholesterolemic agents in vivo. Examn. of the structure activity relationships in the Ph ring and alkyl portion of the N-phenyl-N'-alkylureas revealed that 2,6-diisopropyl substitution was optimal in the Ph ring, for example in .N-(2,6-diisopropylphenyl)-N'-decylurea (I). When the 2,6-diisopropyl moiety was kept const., potency in vitro and in vivo was maintained with straight and branched alkyl groups from 6 to 18 carbons in length. Only replacement of amide bonds with isosteres having both hydrogen bond donor and acceptor functionalities yielded compds. retaining ACAT inhibitory activity. Replacement of the amide bond with the urea bioisostere yielded compds. that were potent ACAT inhibitors in vitro and efficacious hypocholesterolemic agents in vivo. Examn. of the structure activity relationships in the Ph ring and alkyl portion of the N-phenyl-N'-alkylureas revealed that 2,6-diisopropyl substitution was optimal in the Ph ring. When the 2,6-diisopropyl moiety was kept const., potency in vitro and in vivo was maintained with straight and branched alkyl groups from 6 to 18 carbons in length.
- 208Augelli-Szafran, C. E.; Blankley, C. J.; Roth, B. D.; Trivedi, B. K.; Bousley, R. F.; Essenburg, A. D.; Hamelehle, K. L.; Krause, B. R.; Stanfield, R. L. Inhibitors of acyl-CoA:cholesterol acyltransferase. 5. identification and structure-activity relationships of novel beta-ketoamides as hypocholesterolemic agents. J. Med. Chem. 1993, 36, 2943– 2949, DOI: 10.1021/jm00072a014[ACS Full Text], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXlvFGis7Y%253D&md5=f81c99fccade9b20cf5e4781ab274706Inhibitors of acyl-CoA:cholesterol acyltransferase. 5. Identification and structure-activity relationships of novel β-keto amides as hypocholesterolemic agentsAugelli-Szafran, Corinne E.; Blankley, C. John; Roth, Bruce D.; Trivedi, Bharat K.; Bousley, Richard F.; Essenburg, Arnold D.; Hamelehle, Katherine L.; Krause, Brian R.; Stanfield, Richard L.Journal of Medicinal Chemistry (1993), 36 (20), 2943-9CODEN: JMCMAR; ISSN:0022-2623.A study of structure-activity relations of substituted β-ketoamide acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors (I, R1,R5,R6 = e.g., H or alkyl; R2,R3 = H or Me; R4 = C8-13 alkyl, Ph, CHPh2) and (II, X = O or NH, R = C5-6 alkyl or dodecyl; n = 1-3) was performed. Whereas the β-keto group was tolerated with no loss in activity, β-hydroxy and oxime moieties led to significantly reduced activity in vitro and in vivo. The most potent inhibitor from the acyclic series (III; IC50 = 0.006 μM) contained a C13-alkyl chain. III reduced plasma total cholesterol by 38% and 66% at 3 and 30 mg/kg, resp., in cholesterol-fed rats. Dimethylation α to the anilide core and subsequent N-methylation of the amide-NH decreased in vitro potency significantly. High potency was retained with inhibitors which incorporated the carbonyl into a lactam ring.
- 209Trivedi, B. K.; Holmes, A.; Stoeber, T. L.; Blankley, C. J.; Roark, W. H.; Picard, J. A.; Shaw, M. K.; Essenburg, A. D.; Stanfield, R. L.; Krause, B. R. Inhibitors of acyl-Coa:cholesterol acyltransferase. 4. a novel series of urea ACAT inhibitors as potential hypocholesterolemic agents. J. Med. Chem. 1993, 36, 3300– 3307, DOI: 10.1021/jm00074a011[ACS Full Text], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXlsVaqsg%253D%253D&md5=93453fd181d47a1dbd608ccb274652cfInhibitors of acyl-CoA:cholesterol acyltransferase. 4. A novel series of urea ACAT inhibitors as potential hypocholesterolemic agentsTrivedi, Bharat K.; Holmes, Ann; Stoeber, Terri L.; Blankley, C. John; Roark, W. Howard; Picard, Joseph A.; Shaw, Mary K.; Essenburg, Arnold D.; Stanfield, Richard L.; Krause, Brian R.Journal of Medicinal Chemistry (1993), 36 (22), 3300-7CODEN: JMCMAR; ISSN:0022-2623.A series of N-phenyl-N'-aralkyl- and N-phenyl-N'-(1-phenylcycloalkyl)ureas has been synthesized as inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). This intracellular enzyme is thought to be responsible for the esterification of dietary cholesterol; hence inhibition of this enzyme could reduce diet-induced hypercholesterolemia. For this series of compds., the in vitro ACAT inhibitory activity was improved by increasing the bulk of the 2,6-substituents on the Ph ring. Spacing of the arom. rings was crit. for the ACAT inhibitory activity. A Ph ring five atoms away from the requisite 2,6-diisopropylphenyl moiety was optimal for in vitro activity. Substitution α to the N'-Ph moiety enhanced in vitro potency. In the case of phenylcycloalkyl ureas, ACAT inhibitory activity was independent of the size of the cycloalkyl ring. From this series of analogs, compd. I, which had excellent in vitro potency for inhibiting ACAT, was found to lower plasma cholesterol by 73% in vivo when administered in the diet at 50 mg/kg in an animal model of hypercholesterolemia. In this model, compd. I lowered plasma cholesterol dose dependently and was as efficacious as the Lederle ACAT inhibitor CL 277082.
- 210Lebreton, L.; Annat, J.; Derrepas, P.; Dutartre, P.; Renaut, P. Structure-immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 1. structural modifications of the hydroxyglycine moiety. J. Med. Chem. 1999, 42, 277– 290, DOI: 10.1021/jm980431g[ACS Full Text], [CAS], Google Scholar210https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXhslOhtg%253D%253D&md5=93b77bb48c6d2fa8cfa1c3bcf4aa3e84Structure-Immunosuppressive Activity Relationships of New Analogs of 15-Deoxyspergualin. 1. Structural Modifications of the Hydroxyglycine MoietyLebreton, Luc; Annat, Jocelyne; Derrepas, Philippe; Dutartre, Patrick; Renaut, PatriceJournal of Medicinal Chemistry (1999), 42 (2), 277-290CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of new analogs of 15-deoxyspergualin (DSG), an immunosuppressive agent currently commercialized in Japan, was synthesized and tested in a graft-vs.-host disease (GVHD) model in mice. Using the general concept of bioisosteric replacement, variations of the hydroxyglycine central "C" region were made in order to det. its optimum structure in terms of in vivo immunosuppressive activity. By this way, the malonic deriv. H2NC(=NH)NH(CH2)6NHCOCH2CONH(CH2)4NH(CH2)3NH2 (I) was discovered as the first example of a new series of potent immunosuppressive agents encompassing a retro-amide bond linked to the hexyl-guanidino moiety. Structure-activity relationships of this series were studied by synthesizing compds. H2NC(=NH)NH(CH2)6NHCOACONH(CH2)4NH(CH2)3NH2 (II) [A = CH2, (Z)-CH=CH, (CH2)2, (CH2)3, bond, (E)-CH=CH, CH(CH2Ph), CH(Me), CH(OMe), CH2CH(OH), CH(Ph), C(CH2OH)2, CH(Et), C(Me)2, CH(NHAc), CH(NH2), C(OMe)2, CH(OCH2Ph), CH(OH), CH(F)]. Variation of the "right-amide" of I led to the urea H2NC(=NH)NH(CH2)6NHCOCH2NHCONH(CH2)4NH(CH2)3NH2 and the carbamates H2NC(=NH)NH(CH2)6NHCOCH2NHCOO(CH2)4NH(CH2)3NH2 and H2NC(=NH)NH(CH2)6NHCOCH2OCONH(CH2)4NH(CH2)3NH2 (III) which proved to be equally active as DSG in our GVHD model. III was found to be the most potent deriv., being slightly more active than DSG in a heart allotransplantation model in rats. Due to the absence of chiral center in its structure and to its improved chem. stability compared to DSG, III was selected as a candidate for clin. evaluation.
- 211Chan, L.; Jin, H.; Stefanac, T.; Lavallee, J. F.; Falardeau, G.; Wang, W.; Bedard, J.; May, S.; Yuen, L. Discovery of 1,6-naphthyridines as a novel class of potent and selective human cytomegalovirus inhibitors. J. Med. Chem. 1999, 42, 3023– 3025, DOI: 10.1021/jm9902483[ACS Full Text], [CAS], Google Scholar211https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXksF2lu78%253D&md5=d2c1ab14066985ba2e9306901cb37fceDiscovery of 1,6-Naphthyridines as a Novel Class of Potent and Selective Human Cytomegalovirus InhibitorsChan, Laval; Jin, Haolun; Stefanac, Tomislav; Lavallee, Jean-Francois; Falardeau, Guy; Wang, Wei; Bedard, Jean; May, Suzanne; Yuen, LeonardJournal of Medicinal Chemistry (1999), 42 (16), 3023-3025CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The design and synthesis of analogs of 1,6-naphthyridine as human cytomegalovirus inhibitors as well as the results of preliminary structure-activity relation (SAR) studies are described. The SAR investigation suggests that an isopropoxy group at the ortho position and substitution at C-8 are highly desirable.
- 212Chan, L.; Jin, H.; Stefanac, T.; Wang, W.; Lavallee, J. F.; Bedard, J.; May, S. Isoquinoline-6-carboxamides as potent and selective anti-human cytomegalovirus (HCMV) inhibitors. Bioorg. Med. Chem. Lett. 1999, 9, 2583– 2586, DOI: 10.1016/S0960-894X(99)00435-7[Crossref], [PubMed], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXmtFCitrw%253D&md5=ccf74cabd354a03db550b009442a8c6fIsoquinoline-6-carboxamides as potent and selective anti-human cytomegalovirus (HCMV) inhibitorsChan, Laval; Jin, Haolun; Stefanac, Tomislav; Wang, Wei; Lavallee, Jean-Francois; Bedard, Jean; May, SuzanneBioorganic & Medicinal Chemistry Letters (1999), 9 (17), 2583-2586CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Structure-activity relationship studies on newly identified anti-HCMV compds., the 1,6-naphthyridines led to the identification of isoquinoline-6-carboxamides as potent and selective anti-HCMV agents.
- 213Chan, L.; Stefanac, T.; Lavallee, J. F.; Jin, H.; Bedard, J.; May, S.; Falardeau, G. Design and synthesis of new potent human cytomegalovirus (HCMV) inhibitors based on internally hydrogen-bonded 1,6-naphthyridines. Bioorg. Med. Chem. Lett. 2001, 11, 103– 105, DOI: 10.1016/S0960-894X(00)00607-7[Crossref], [PubMed], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXotlKnug%253D%253D&md5=4626a7f37f6207672b925d79c07c0164Design and synthesis of new potent human cytomegalovirus (HCMV) inhibitors based on internally hydrogen-bonded 1,6-naphthyridinesChan, L.; Stefanac, T.; Lavallee, J.-F.; Jin, H.; Bedard, J.; May, S.; Falardeau, G.Bioorganic & Medicinal Chemistry Letters (2001), 11 (2), 103-105CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)1,6-Naphthyridine-2-carboxylic acid benzylamides are potent anti-HCMV compds. Replacement of the amide moiety by other groups contg. internal hydrogen bonds was undertaken to extend the structure-activity relationship. The results indicated that the urea derivs. showed very good activity.
- 214Bielawska, A.; Greenberg, M. S.; Perry, D.; Jayadev, S.; Shayman, J. A.; McKay, C.; Hannun, Y. A. (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol as an inhibitor of ceramidase. J. Biol. Chem. 1996, 271, 12646– 12654, DOI: 10.1074/jbc.271.21.12646[Crossref], [PubMed], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjtFantLg%253D&md5=1ed01f1936e1d2a9dcbd9b4b137ebbaa(1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol as an inhibitor of ceramidaseBielawska, Alicja; Greenberg, Mathew S.; Perry, David; Jayadev, Supriya; Shayman, James A.; McKay, Charles; Hannun, Yusuf A.Journal of Biological Chemistry (1996), 271 (21), 12646-12654CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The cellular and biochem. activities of the ceramide analog, (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol (D-e-MAPP), were examd. The addn. of 5 μM D-e-MAPP to HL-60 human promyelocytic leukemia cells resulted in a concn.- and time-dependent growth suppression accompanied by an arrest in the G0/G1 phase of the cell cycle; thus mimicking the action of exogenous ceramides. Its enantiomer, L-e-MAPP, was without effect. Two lines of evidence suggested that D-e-MAPP may not function as a direct analog of ceramide. First, D-e-MAPP possesses a stereochem. configuration opposite to that of D-erythro-ceramide. Second, D-e-MAPP failed to activate ceramide-activated phosphoprotein phosphatase in vitro. Therefore, the authors examd. if D-e-MAPP functioned indirectly by modulating endogenous ceramide levels. The addn. of D-e-MAPP to cells, but not L-e-MAPP, caused a time- and concn.-dependent elevation in endogenous ceramide levels reaching >3-fold over baseline following 24 h of treatment. Both D-e-MAPP and L-e-MAPP underwent similar uptake by HL-60 cells. D-E-MAPP was poorly metabolized, and remained intact in cells, whereas L-e-MAPP underwent a time- and concn.-dependent metab., primarily through N-deacylation. In vitro, L-e-MAPP was metabolized by alk. ceramidase to an extent similar to that seen with C16-ceramide. D-E-MAPP was not metabolized. Instead, D-e-MAPP inhibited alk. ceramidase activity in vitro with an IC50 of 1-5 μM. D-E-MAPP did not modulate the activity of other ceramide-metabolizing enzymes in vitro or in cells, and it was a poor inhibitor of acid ceramidase (IC50 > 500 μM). Finally, D-e-MAPP inhibited the metab. of L-e-MAPP in cells. These studies demonstrate that D-e-MAPP functions as an inhibitor of alk. ceramidase in vitro and in cells resulting in elevation in endogenous levels of ceramide with the consequent biol. effects of growth suppression and cell cycle arrest. These studies point to an important role for ceramidases in the regulation of endogenous levels of ceramide.
- 215Selzner, M.; Bielawska, A.; Morse, M. A.; Rudiger, H. A.; Sindram, D.; Hannun, Y. A.; Clavien, P. A. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res. 2001, 61, 1233– 1240[PubMed], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhsFSqsLg%253D&md5=8ac97b8e71f9bfd0dcbbf65975d5f167Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancerSelzner, Markus; Bielawska, Alicja; Morse, Michael A.; Rudiger, Hannes A.; Sindram, David; Hannun, Yusuf A.; Clavien, Pierre-AlainCancer Research (2001), 61 (3), 1233-1240CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Dysfunction in the physiol. pathways of programmed cell death may promote proliferation of malignant cells, and correction of such defects may selectively induce apoptosis in cancer cells. We measured the levels of ceramide, a candidate lipid mediator of apoptosis, in human metastatic colorectal cancer and tested in vitro and in vivo effects of various ceramide analogs in inducing apoptosis in metastatic colon cancer. Human colon cancer showed a >50% decrease in the cellular content of ceramide when compared with normal colon mucosa. Application of ceramide analogs and ceramidase inhibitors induced rapid cell death through activation of various proapoptotic mols., such as caspases and release of cytochrome c. Ceramidase inhibition increases the ceramide content of tumor cells, resulting in max. activation of the apoptotic cascade. Normal liver cells were completely resistant to inhibitors of ceramidases. Treatment of nude mice with B13, the most potent ceramidase inhibitor, completely prevented tumor growth using two different aggressive human colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogs of ceramide and inhibitors of ceramidases offer a promising therapeutic strategy with selective toxicity toward malignant but not normal cells. These studies also suggest that the ceramide content in cancer cells might be involved in the pathogenesis of tumor growth in vitro and in vivo.
- 216Lim, S.; Ryu, J. H.; Im, C.; Yim, C. B. Synthesis and cytotoxicity of new 3-alkyl-1-(1-methyl-2-phenylethyl)ureas related to ceramide. Arch. Pharmacal Res. 2003, 26, 270– 274, DOI: 10.1007/BF02976954[Crossref], [PubMed], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjvV2hu78%253D&md5=55eccdc6c14b998a3f92699eacf4b29aSynthesis and cytotoxicity of new 3-alkyl-1-(1-methyl-2-phenylethyl)ureas related to ceramideLim, Sejin; Ryu, Jae Hark; Im, Chaeuk; Yim, Chul BuArchives of Pharmacal Research (2003), 26 (4), 270-274CODEN: APHRDQ; ISSN:0253-6269. (Pharmaceutical Society of Korea)A series of new 3-alkyl-1-(1-methyl-2-phenylethyl)ureas related to ceramide was synthesized and evaluated for their in vitro cytotoxic activity against five human tumor cell lines. The urea analog of B13 showed comparable or slightly more potent cytotoxic activity as compared to B13, indicating that urea does appear to serve as a bioisostere of amide.
- 217Chang, Y. T.; Choi, J.; Ding, S.; Prieschl, E. E.; Baumruker, T.; Lee, J. M.; Chung, S. K.; Schultz, P. G. The synthesis and biological characterization of a ceramide library. J. Am. Chem. Soc. 2002, 124, 1856– 1857, DOI: 10.1021/ja017576o[ACS Full Text], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xps1aisg%253D%253D&md5=08e8c91553b4795803934d0671173366The Synthesis and Biological Characterization of a Ceramide LibraryChang, Young-Tae; Choi, Jaehwa; Ding, Sheng; Prieschl, Eva E.; Baumruker, Thomas; Lee, Jae-Mok; Chung, Sung-Kee; Schultz, Peter G.Journal of the American Chemical Society (2002), 124 (9), 1856-1857CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A facile synthesis of a combinatorial ceramide library and their activities in the NF-κB pathway and in apoptosis induction/prevention were demonstrated. A novel NF-κB activating mol. was discovered among ceramide contg. β-galactose, and the structural requirements of ceramides for apoptosis induction was elucidated.
- 218Bieberich, E.; Hu, B.; Silva, J.; MacKinnon, S.; Yu, R. K.; Fillmore, H.; Broaddus, W. C.; Ottenbrite, R. M. Synthesis and characterization of novel ceramide analogs for induction of apoptosis in human cancer cells. Cancer Lett. 2002, 181, 55– 64, DOI: 10.1016/S0304-3835(02)00049-6[Crossref], [PubMed], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XivVSgur0%253D&md5=14c8ac8985f6b711c5adb3ca2dbaf033Synthesis and characterization of novel ceramide analogs for induction of apoptosis in human cancer cellsBieberich, Erhard; Hu, Bin; Silva, Jeane; MacKinnon, Sarah; Yu, Robert K.; Fillmore, Helen; Broaddus, William C.; Ottenbrite, Raphael M.Cancer Letters (Shannon, Ireland) (2002), 181 (1), 55-64CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Science Ireland Ltd.)A variety of anti-cancer drugs elevate endogenous ceramide, thereby inducing apoptosis in tumor cells. Recently, we have introduced novel ceramide analogs of the β-hydroxy alkyl amide type, which trigger pro-apoptotic signaling pathways without prior elevation of endogenous ceramide. They induce apoptosis specifically in rapidly dividing neuroblastoma cells, but not in resting or differentiated cells. We characterize new ceramide mimics that have been derived from N-acylation of serinol , diethanolamine, propanolamine , and tris(hydroxy-methyl)methylamine with myristic, palmitic, or oleic acid. The water soly. of these compds. exceeds that of ceramide by more than 100-fold (up to 5 mM). Apoptosis of human neuroblastoma, glioma, medulloblastoma, and adenocarcinoma cells is induced by N-(2-hydroxy-1-(hydroxymethyl)ethyl)-palmitoylamide, C16-serinol, N-(2-hydroxy-1-(hydroxymethyl)ethyl)-oleoylamide, C18-serinol , N-bis(2-hydroxyethyl)-myristoyl-amide , and N-tris(hydroxymethyl)methyl-oleoylamide within 60 min of incubation, and is completed even after removal of the compd. from the medium. This is most likely due to a rapid uptake of the analogs followed by their slow release from the cells. Alteration of the acyl chain length to less than 14 methylene units, removal of the amino group, or reducing the no. of hydroxyalkyl residues to less than two significantly lowers or eliminates the pro-apoptotic potential of these compds. The target specificity of novel ceramide analogs for tumor cells, their water soly., and fast pro-apoptotic mechanism indicates a high therapeutic potential for cancer treatment.
- 219Wang, H.; Huwaimel, B.; Verma, K.; Miller, J.; Germain, T. M.; Kinarivala, N.; Pappas, D.; Brookes, P. S.; Trippier, P. C. Synthesis and antineoplastic evaluation of mitochondrial complex II (succinate dehydrogenase) inhibitors derived from Atpenin A5. ChemMedChem 2017, 12, 1033– 1044, DOI: 10.1002/cmdc.201700196[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpsFSqsLg%253D&md5=0c9cbe31b6f518e8a37fc1aa3beac02bSynthesis and Antineoplastic Evaluation of Mitochondrial Complex II (Succinate Dehydrogenase) Inhibitors Derived from Atpenin A5Wang, Hezhen; Huwaimel, Bader; Verma, Kshitij; Miller, James; Germain, Todd M.; Kinarivala, Nihar; Pappas, Dimitri; Brookes, Paul S.; Trippier, Paul C.ChemMedChem (2017), 12 (13), 1033-1044CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Mitochondrial complex II (CII) is an emerging target for numerous human diseases. Sixteen analogs of the CII inhibitor natural product atpenin A5 were prepd. to evaluate the structure-activity relationship of the C5 pyridine side chain. The side chain ketone moiety was detd. to be pharmacophoric, engendering a bioactive conformation. One analog, 1-(2,4-dihydroxy-5,6-dimethoxypyridin-3-yl)hexan-1-one (16 c), was found to have a CII IC50 value of 64 nM, to retain selectivity for CII over mitochondrial complex I (>156-fold), and to possess a ligand-lipophilicity efficiency (LLE) of 5.62, desirable metrics for a lead compd. This deriv. and other highly potent CII inhibitors show potent and selective anti-proliferative activity in multiple human prostate cancer cell lines under both normoxia and hypoxia, acting to inhibit mitochondrial electron transport.
- 220Patrick, D. A.; Wenzler, T.; Yang, S.; Weiser, P. T.; Wang, M. Z.; Brun, R.; Tidwell, R. R. Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiense. Bioorg. Med. Chem. 2016, 24, 2451– 2465, DOI: 10.1016/j.bmc.2016.04.006[Crossref], [PubMed], [CAS], Google Scholar220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmtlegtLk%253D&md5=d371dc632576f40e4002cd96b67c5a77Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiensePatrick, Donald A.; Wenzler, Tanja; Yang, Sihyung; Weiser, Patrick T.; Wang, Michael Zhuo; Brun, Reto; Tidwell, Richard R.Bioorganic & Medicinal Chemistry (2016), 24 (11), 2451-2465CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)2-(2-Benzamido)ethyl-4-phenylthiazole I was one of 1035 mols. (grouped into 115 distinct scaffolds) found to be inhibitory to Trypanosoma brucei, the pathogen causing human African trypanosomiasis, at concns. below 3.6 μM and nontoxic to mammalian (Huh7) cells in a phenotypic high-throughput screen of a 700,000 compd. library performed by the Genomics Institute of the Novartis Research Foundation (GNF). Compd. I and 72 analogs were synthesized in this lab. by one of two general pathways. These plus 10 com. available analogs were tested against T. brucei rhodesiense STIB900 and L6 rat myoblast cells (for cytotoxicity) in vitro. Forty-four derivs. were more potent than I, including eight with IC50 values below 100 nM. The most potent and most selective for the parasite was the urea analog 2-(2-piperidin-1-ylamido)ethyl-4-(3-fluorophenyl)thiazole II (IC50 = 9 nM, SI > 18,000). None of 33 compds. tested were able to cure mice infected with the parasite; however, seven compds. caused temporary redns. of parasitemia (≥97%) but with subsequent relapses. The lack of in vivo efficacy was at least partially due to their poor metabolic stability, as demonstrated by the short half-lives of 15 analogs against mouse and human liver microsomes.
- 221Patrick, D. A.; Gillespie, J. R.; McQueen, J.; Hulverson, M. A.; Ranade, R. M.; Creason, S. A.; Herbst, Z. M.; Gelb, M. H.; Buckner, F. S.; Tidwell, R. R. Urea derivatives of 2-aryl-benzothiazol-5-amines: a new class of potential drugs for human African trypanosomiasis. J. Med. Chem. 2017, 60, 957– 971, DOI: 10.1021/acs.jmedchem.6b01163[ACS Full Text], [CAS], Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitV2lt7nN&md5=aaf065ffbba4f4e702119f9c4c81d822Urea Derivatives of 2-Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African TrypanosomiasisPatrick, Donald A.; Gillespie, J. Robert; McQueen, Joshua; Hulverson, Matthew A.; Ranade, Ranae M.; Creason, Sharon A.; Herbst, Zackary M.; Gelb, Michael H.; Buckner, Frederick S.; Tidwell, Richard R.Journal of Medicinal Chemistry (2017), 60 (3), 957-971CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A previous publication from this lab explored the antitrypanosomal activities of novel derivs. of 2-(2-benzamido)ethyl-4-phenylthiazole, which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a no. of these compds., particularly the urea analogs, were quite potent, these mols. as a whole exhibited poor metabolic stability. The present work describes the synthesis of 65 new analogs arising from medicinal chem. optimization at different sites on the mol. The most promising compds. were the urea derivs. of 2-aryl-benzothiazol-5-amines. One such analog, (S)-2-(3,4-difluorophenyl)-5-(3-fluoro-N-pyrrolidylamido)benzothiazole (I) was chosen for in vivo efficacy studies based upon in vitro activity, metabolic stability, and brain penetration. This compd. attained 5/5 cures in murine models of both early and late stage human African trypanosomiasis, representing a new lead for the development of drugs to combat this neglected disease.
- 222He, J. B.; Ren, Y. L.; Sun, Q. S.; You, G. Y.; Zhang, L.; Zou, P.; Feng, L. L.; Wan, J.; He, H. W. Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors. Bioorg. Med. Chem. 2014, 22, 3180– 3186, DOI: 10.1016/j.bmc.2014.04.003[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnsVWqsbs%253D&md5=d5fdc148d0188b8f2c4ba703a0dc27a0Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitorsHe, Jun-Bo; Ren, Yan-Liang; Sun, Qiu-Shuang; You, Ge-Yun; Zhang, Li; Zou, Peng; Feng, Ling-Ling; Wan, Jian; He, Hong-WuBioorganic & Medicinal Chemistry (2014), 22 (12), 3180-3186CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)By targeting the ThDP binding site of Escherichia coli PDHc-E1, two new 'open-chain' classes of E. coli PDHc-E1 inhibitors, amide and urea derivs., were designed, synthesized, and evaluated. The amide deriv. I showed the most potent inhibition of E. coli PDHc-E1. The urea derivs. displayed more potent inhibitory activity than the corresponding amide derivs. with the same substituent. Mol. docking studies confirmed that the urea derivs. have more potency due to the two hydrogen bonds formed by two NH of urea with Glu522. The docking results also indicate it might help us to design more efficient PDHc-E1 inhibitors that could interact with Glu522.
- 223Ghosh, A. K.; Brindisi, M. Organic carbamates in drug design and medicinal chemistry. J. Med. Chem. 2015, 58, 2895– 2940, DOI: 10.1021/jm501371s[ACS Full Text], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXltVWkuw%253D%253D&md5=e3548247931b74b60e299ada1e27dda5Organic Carbamates in Drug Design and Medicinal ChemistryGhosh, Arun K.; Brindisi, MargheritaJournal of Medicinal Chemistry (2015), 58 (7), 2895-2940CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The carbamate group is a key structural motif in many approved drugs and prodrugs. There is an increasing use of carbamates in medicinal chem. and many derivs. are specifically designed to make drug-target interactions through their carbamate moiety. In this Perspective, we present properties and stabilities of carbamates, reagents and chem. methodologies for the synthesis of carbamates, and recent applications of carbamates in drug design and medicinal chem.
- 224Eckhardt, B. J.; Gulick, R. M. Drugs for HIV Infection. In Infectious Diseases, 4th ed.; Cohen, J., Opal, S. M., Powderly, W. G., Ed.; Elsevier Ltd., 2017; pp 1293– 1308.
- 225Bursavich, M. G.; Rich, D. H. Designing non-peptide peptidomimetics in the 21st century: inhibitors targeting conformational ensembles. J. Med. Chem. 2002, 45, 541– 558, DOI: 10.1021/jm010425b[ACS Full Text], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmsVantw%253D%253D&md5=8f00dc08b4d51c3021dd22a247bd56c0Designing Non-Peptide Peptidomimetics in the 21st Century: Inhibitors Targeting Conformational EnsemblesBursavich, Matthew G.; Rich, Daniel H.Journal of Medicinal Chemistry (2002), 45 (3), 541-558CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The goal of this Perspective is to outline for medicinal chemists the potential impact of receptor conformational mobility on rational drug design. While others have postulated receptor-based conformational selection of ligands and successfully designed inhibitors to emulate the -strand binding motif of native ligands , we show that novel protein conformations (not obsd. in either native or enzyme-inhibitor complexes) can be exploited to create nonpeptide enzyme inhibitors. We begin with a review of the development of peptidomimetic aspartic peptidase inhibitors and conclude with a new proposal for discovering fundamentally novel nonpeptide peptidomimetics by targeting conformational ensembles. Although we focus on the aspartic peptidases, the lessons derived therein are applicable to other peptidase and receptor-ligand systems.
- 226Ghosh, A. K.; Thompson, W. J.; McKee, S. P.; Duong, T. T.; Lyle, T. A.; Chen, J. C.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. 3-Tetrahydrofuran and pyran urethanes as high-affinity P2-ligands for HIV-1 protease inhibitors. J. Med. Chem. 1993, 36, 292– 294, DOI: 10.1021/jm00054a015[ACS Full Text], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXnsF2ltA%253D%253D&md5=f7046b53447fa4fdb531d0a18aa3643c3-Tetrahydrofuran and pyran urethanes as high-affinity P2-ligands for HIV-1 protease inhibitorsGhosh, Arun K.; Thompson, Wayne J.; McKee, Sean P.; Duong, Tien T.; Lyle, Terry A.; Chen, Jenny C.; Darke, Paul L.; Zugay, Joan A.; Emini, Emilio A.; et al.Journal of Medicinal Chemistry (1993), 36 (2), 292-4CODEN: JMCMAR; ISSN:0022-2623.Urethanes of 3-tetrahydrofurans and pyrans are high affinity P2 ligands for the HIV-1 protease inhibitors. Incorporation of these ligands provided potent inhibitors in the hydroxyethylene and hydroxyethylamine series with picomolar and nanomolar in vitro potencies. Substitution of t-butyloxycarbonyl group in I either with 3-tetrahydrofuranyl or 3-tetrahydropyranyl urethane not only increases intrinsic potency against the enzyme but generally leads to significant enhancement of antiviral potency as well. For example, II (IC50 <0.03 nM), obtained from com. available 3-(S)-hydroxytetrahydrofuran has prevented the spread of HIV-1 at a concn. of 3 nM (CIC95), a greater than 133-fold potency enhancement over inhibitor I.
- 227Thompson, W. J.; Ghosh, A. K.; Holloway, M. K.; Lee, H. Y.; Munson, P. M.; Schwering, J. E.; Wai, J.; Darke, P. L.; Zugay, J.; Emini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. 3′-Tetrahydrofuranylglycine as a novel, unnatural amino acid surrogate for asparagine in the design of inhibitors of the HIV protease. J. Am. Chem. Soc. 1993, 115, 801– 803, DOI: 10.1021/ja00055a069[ACS Full Text], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXht1Gjsbs%253D&md5=ea089d154011286bb01975430f67e6ef3'-Tetrahydrofuranylglycine as a novel, unnatural amino acid surrogate for asparagine in the design of inhibitors of the HIV proteaseThompson, Wayne J.; Ghosh, Arun K.; Holloway, M. Katharine; Lee, Hee Yoon; Munson, Peter M.; Schwering, John E.; Wai, Jenny; Darke, Paul L.; Zugay, Joan; et al.Journal of the American Chemical Society (1993), 115 (2), 801-3CODEN: JACSAT; ISSN:0002-7863.The stereoselective synthesis of the novel amino acids (3'R)- and (3'S)-tetrahydrofuranylglycine are reported. When incorporated into hydroxyethylamine transition state isostere I [R = (R)- and (S)-tetrahydrofuryl], substantial improvements in the inhibitory activities against HIV-1 and HIV-2 protease were obsd. relative to asparagine analog I (R = CH2CONH2) (Ro 31-8959).
- 228Ghosh, A. K.; Thompson, W. J.; Holloway, M. K.; McKee, S. P.; Duong, T. T.; Lee, H. Y.; Munson, P. M.; Smith, A. M.; Wai, J. M.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. Potent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands. J. Med. Chem. 1993, 36, 2300– 2310, DOI: 10.1021/jm00068a006[ACS Full Text], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmtVegtbs%253D&md5=63f60b2efd113d4f2f51d869b4a4970bPotent HIV protease inhibitors: the development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligandsGhosh, Arun K.; Thompson, Wayne J.; Holloway, M. Katharine; McKee, Sean P.; Duong, Tien T.; Lee, Hee Yoon; Munson, Peter M.; Smith, Anthony M.; Wai, Jenny M.; et al.Journal of Medicinal Chemistry (1993), 36 (16), 2300-10CODEN: JMCMAR; ISSN:0022-2623.A series of protease inhibitors bearing constrained unnatural amino acids at the P2-position and novel heterocycles at the P3-position of compd. I (R = R1; Ro 31-8959) were synthesized, and their in vitro enzyme inhibitory and antiviral activities were evaluated. Replacement of P2-asparagine of compd. I (R = R1) with (2S,3'R)-tetrahydrofuranylglycine resulted in improvement in enzyme inhibitory as well as antiviral potencies (compd. I; R = R2). Interestingly, incorporation of (2S,3'S)-tetrahydrofuranylglycine at the P2-position proved to be less effective. The resulting compd. I (R = R3) was 100-fold less potent than the 2S,3R-isomer (compd. I; R = R2). This stereochem. preference indicated a hydrogen-bonding interaction between the tetrahydrofuranyl oxygen and the residues of the S2-region of the enzyme active site. Furthermore, replacement of P3-quinolinoyl ligand of I (R = R1) with various novel heterocycles resulted in potent inhibitors of HIV proteases. Of particular interest, compd. I (R = R4) with (2S,3'R)-tetrahydrofuranylglycine at P2 and pyrazine deriv. at P3 is one of the most potent inhibitors of HIV-1 (IC50 value 0.07 nM) and HIV-2 (IC50 value 0.18 nM) proteases. Another important result in this series is the identification of compd. I (R = R5) in which the P2-P3-amide carbonyl has been removed. The resulting compd. I (R = R5) has exhibited improvement in antiviral potency while retaining the enzyme inhibitory potency similar to compd. I (R = R1).
- 229Morsy, A.; Trippier, P. C. Current and emerging pharmacological targets for the treatment of Alzheimer’s disease. J. Alzheimer's Dis. 2019, 72, S145– S176, DOI: 10.3233/JAD-190744[Crossref], [PubMed], [CAS], Google Scholar229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXosFKn&md5=95773aaf90f1f70bf76afd9112bfc776Current and Emerging Pharmacological Targets for the Treatment of Alzheimer's DiseaseMorsy, Ahmed; Trippier, Paul C.; Reddy, P. HemachandraJournal of Alzheimer's Disease (2019), 72 (s1), S145-S176CODEN: JADIF9; ISSN:1387-2877. (IOS Press)A review. No cure or disease-modifying therapy for Alzheimer's disease (AD) has yet been realized. However, a multitude of pharmacol. targets have been identified for possible engagement to enable drug discovery efforts for AD. Herein, we review these targets comprised around three main therapeutic strategies. First is an approach that targets the main pathol. hallmarks of AD: amyloid-β (Aβ) oligomers and hyperphosphorylated tau tangles which primarily focuses on reducing formation and aggregation, and/or inducing their clearance. Second is a strategy that modulates neurotransmitter signaling. Comprising this strategy are the cholinesterase inhibitors and N-methyl-D-aspartate receptor blockade treatments that are clin. approved for the symptomatic treatment of AD. Addnl. targets that aim to stabilize neuron signaling through modulation of neurotransmitters and their receptors are also discussed. Finally, the third approach comprises a collection of 'sensitive targets' that indirectly influence Aβ or tau accumulation. These targets are proteins that upon Aβ accumulation in the brain or direct Aβ-target interaction, a modification in the target's function is induced. The process occurs early in disease progression, ultimately causing neuronal dysfunction. This strategy aims to restore normal target function to alleviate Aβ-induced toxicity in neurons. Overall, we generally limit our anal. to targets that have emerged in the last decade and targets that have been validated using small mols. in in vitro and/or in vivo models. This review is not an exhaustive list of all possible targets for AD but serves to highlight the most promising and crit. targets suitable for small mol. drug intervention.
- 230Wong, G. T.; Manfra, D.; Poulet, F. M.; Zhang, Q.; Josien, H.; Bara, T.; Engstrom, L.; Pinzon-Ortiz, M.; Fine, J. S.; Lee, H. J.; Zhang, L.; Higgins, G. A.; Parker, E. M. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J. Biol. Chem. 2004, 279, 12876– 12882, DOI: 10.1074/jbc.M311652200[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXitl2gtb0%253D&md5=c06325df88c961273ac6229e4577d803Chronic Treatment with the γ-Secretase Inhibitor LY-411575 Inhibits β-Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell DifferentiationWong, Gwendolyn T.; Manfra, Denise; Poulet, Frederique M.; Zhang, Qi; Josien, Hubert; Bara, Thomas; Engstrom, Laura; Pinzon-Ortiz, Maria; Fine, Jay S.; Lee, Hu-Jung J.; Zhang, Lili; Higgins, Guy A.; Parker, Eric M.Journal of Biological Chemistry (2004), 279 (13), 12876-12882CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Inhibition of γ-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic β-amyloid (Aβ) peptides, is an attractive approach to the treatment of Alzheimer disease. In addn. to APP, however, several other γ-secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by γ-secretase inhibitors could lead to unintended biol. consequences. To study the in vivo consequences of γ-secretase inhibition, the γ-secretase inhibitor LY-411575 was administered to C57BL/6 and TgCRND8 APP transgenic mice for 15 days. Although most tissues were unaffected, doses of LY-411575 that inhibited Aβ prodn. had marked effects on lymphocyte development and on the intestine. LY-411575 decreased overall thymic cellularity and impaired intrathymic differentiation at the CD4-CD8-CD44+CD25+ precursor stage. No effects on peripheral T cell populations were noted following LY-411575 treatment, but evidence for the altered maturation of peripheral B cells was obsd. In the intestine, LY-411575 treatment increased goblet cell no. and drastically altered tissue morphol. These effects of LY-411575 were not seen in mice that were administered LY-D, a diastereoisomer of LY-411575, which is a very weak γ-secretase inhibitor. These studies show that inhibition of γ-secretase has the expected benefit of reducing Aβ in a murine model of Alzheimer disease but has potentially undesirable biol. effects as well, most likely because of the inhibition of Notch processing.
- 231Peters, J. U.; Galley, G.; Jacobsen, H.; Czech, C.; David-Pierson, P.; Kitas, E. A.; Ozmen, L. Novel orally active, dibenzazepinone-based γ-secretase inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 5918– 5923, DOI: 10.1016/j.bmcl.2007.07.078[Crossref], [PubMed], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFSitL7I&md5=6b1045f9decafe3f13320535b085b6e4Novel orally active, dibenzazepinone-based γ-secretase inhibitorsPeters, Jens-Uwe; Galley, Guido; Jacobsen, Helmut; Czech, Christian; David-Pierson, Pascale; Kitas, Eric A.; Ozmen, LaurenceBioorganic & Medicinal Chemistry Letters (2007), 17 (21), 5918-5923CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Structural modifications of the γ-secretase inhibitor, LY411575, led to a malonamide analog (S),(S)-1 with potent inhibitory activity in vitro, but disappointing activity in a mouse model of Alzheimer's disease. Identification and replacement of a metabolically labile position provided an improved compd. (R/S),(S)-13 with high in vitro activity (IC50 = 1.7 nM), and in vivo activity after oral administration (MED = 3 mg/kg). Further modifications gave an equipotent carbamate analog 14 (I) with improved mol. properties.
- 232Fransson, R.; Nordvall, G.; Bylund, J.; Carlsson-Jonsson, A.; Kratz, J. M.; Svensson, R.; Artursson, P.; Hallberg, M.; Sandstrom, A. Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1–7 analogues. ACS Med. Chem. Lett. 2014, 5, 1272– 1277, DOI: 10.1021/ml5002954[ACS Full Text], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVensrnJ&md5=7c45f3cbb6f0a62e6204a184a61d700eExploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance P 1-7 analoguesFransson, Rebecca; Nordvall, Gunnar; Bylund, Johan; Carlsson-Jonsson, Anna; Kratz, Jadel M.; Svensson, Richard; Artursson, Per; Hallberg, Mathias; Sandstroem, AnjaACS Medicinal Chemistry Letters (2014), 5 (12), 1272-1277CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compds. targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics the authors have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compd. Unfortunately, the pharmacophore of this compd. was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogs with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compd. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide.
- 233Kamenecka, T. M.; Park, Y. J.; Lin, L. S.; de Laszlo, S.; McCauley, E. D.; Van Riper, G.; Egger, L.; Kidambi, U.; Mumford, R. A.; Tong, S.; Tang, W.; Colletti, A.; Teffera, Y.; Stearns, R.; MacCoss, M.; Schmidt, J. A.; Hagmann, W. K. Amidines as amide bond replacements in VLA-4 antagonists. Bioorg. Med. Chem. Lett. 2004, 14, 2323– 2326, DOI: 10.1016/j.bmcl.2004.01.100[Crossref], [PubMed], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjtVegs7s%253D&md5=8f2974249b57ad785d8fd1a4d0f86d61Amidines as amide bond replacements in VLA-4 antagonistsKamenecka, Theodore M.; Park, You-Jung; Lin, Linus S.; de Laszlo, Stephen; McCauley, Ermenegilda D.; Van Riper, Gail; Egger, Linda; Kidambi, Usha; Mumford, Richard A.; Tong, Sharon; Tang, Wei; Colletti, Adria; Teffera, Yohannes; Stearns, Ralph; MacCoss, Malcolm; Schmidt, John A.; Hagmann, William K.Bioorganic & Medicinal Chemistry Letters (2004), 14 (9), 2323-2326CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)VLA-4 (α4β1, very late activating antigen-4), a key cell surface integrin plays an important role in inflammation by promoting leukocyte attachment and extravasation from the vasculature into the peripheral tissues. As such, VLA-4 antagonists may be useful in the treatment, prevention, and suppression of diseases where cell adhesion and migration are important such as asthma, rheumatoid arthritis, and multiple sclerosis. Herein, we report on the discovery, synthesis, and biol. evaluation of amidines as small mol. antagonists of VLA-4.
- 234Hagmann, W. K.; Durette, P. L.; Lanza, T.; Kevin, N. J.; de Laszlo, S. E.; Kopka, I. E.; Young, D.; Magriotis, P. A.; Li, B.; Lin, L. S.; Yang, G.; Kamenecka, T.; Chang, L. L.; Wilson, J.; MacCoss, M.; Mills, S. G.; Van Riper, G.; McCauley, E.; Egger, L. A.; Kidambi, U.; Lyons, K.; Vincent, S.; Stearns, R.; Colletti, A.; Teffera, J.; Tong, S.; Fenyk-Melody, J.; Owens, K.; Levorse, D.; Kim, P.; Schmidt, J. A.; Mumford, R. A. The discovery of sulfonylated dipeptides as potent VLA-4 antagonists. Bioorg. Med. Chem. Lett. 2001, 11, 2709– 2713, DOI: 10.1016/S0960-894X(01)00544-3[Crossref], [PubMed], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnsVKmtbY%253D&md5=80df53cefe5c9295c4e76cc67072446bThe discovery of sulfonylated dipeptides as Potent VLA-4 antagonistsHagmann, W. K.; Durette, P. L.; Lanza, T.; Kevin, N. J.; de Laszlo, S. E.; Kopka, I. E.; Young, D.; Magriotis, P. A.; Li, B.; Lin, L. S.; Yang, G.; Kamenecka, T.; Chang, L. L.; Wilson, J.; MacCoss, M.; Mills, S. G.; Van Riper, G.; McCauley, E.; Egger, L. A.; Kidambi, U.; Lyons, K.; Vincent, S.; Stearns, R.; Colletti, A.; Teffera, J.; Tong, S.; Fenyk-Melody, J.; Owens, K.; Levorse, D.; Kim, P.; Schmidt, J. A.; Mumford, R. A.Bioorganic & Medicinal Chemistry Letters (2001), 11 (20), 2709-2713CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Directed screening of a carboxylic acid-contg. combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid mol. gave a sub-nanomolar inhibitor as a lead for medicinal chem. Preliminary metabolic studies led to the discovery of substituted biphenyl derivs. with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.
- 235Choudhary, A.; Raines, R. T. An evaluation of peptide-bond isosteres. ChemBioChem 2011, 12, 1801– 1807, DOI: 10.1002/cbic.201100272[Crossref], [PubMed], [CAS], Google Scholar235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXoslaqurs%253D&md5=fc2aecec1937ace752f82a8817cd670aAn evaluation of peptide-bond isosteresChoudhary, Amit; Raines, Ronald T.ChemBioChem (2011), 12 (12), 1801-1807CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Peptide-bond isosteres can enable a deep interrogation of the structure and function of a peptide or protein by amplifying or attenuating particular chem. properties. Here, the authors examine in detail the electronic, structural, and conformational attributes of 4 such isosteres (thioamides, esters, alkenes, and fluoroalkenes). In particular, the ability of these isosteres to partake in noncovalent interactions is compared with that of the peptide bond. The consequential perturbations provide a useful tool for chem. biologists to reveal new structure-function relations, and to endow peptides and proteins with desirable attributes.
- 236Thorarensen, A.; Wakefield, B. D.; Romero, D. L.; Marotti, K. R.; Sweeney, M. T.; Zurenko, G. E.; Rohrer, D. C.; Han, F.; Bryant, G. L., Jr. Preparation of novel anthranilic acids as antibacterial agents. extensive evaluation of alternative amide bioisosteres connecting the A- and the B-rings. Bioorg. Med. Chem. Lett. 2007, 17, 2823– 2827, DOI: 10.1016/j.bmcl.2007.02.055[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXkslOqu7c%253D&md5=cc2ae8ed70d31a8b136387e558344ea6Preparation of novel anthranilic acids as antibacterial agents. Extensive evaluation of alternative amide bioisosteres connecting the A- and the B-ringsThorarensen, Atli; Wakefield, Brian D.; Romero, Donna L.; Marotti, Keith R.; Sweeney, Michael T.; Zurenko, Gary E.; Rohrer, Douglas C.; Han, Fusen; Bryant, Garold L.Bioorganic & Medicinal Chemistry Letters (2007), 17 (10), 2823-2827CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)The identification of an anthranilic acid lead and the optimization resulting in the advanced lead I was recently described. In this report, the prepn. of several selected amide bioisosteres connecting the two benzene rings are described. The E-alkene provided a rigid analog with equal potency to the corresponding amide. This indicates that the amide is not a recognition element and rather acts as an appropriate spatial linker of the two important aryl rings. The work here clearly demonstrates that the amide linker can be replaced with several functionalities without significant deterioration in the MIC activity.
- 237Volonterio, A.; Bravo, P.; Zanda, M. Synthesis of partially modified retro and retroinverso ψ[NHCH(CF3)]-peptides. Org. Lett. 2000, 2, 1827– 1830, DOI: 10.1021/ol005876p[ACS Full Text], [CAS], Google Scholar237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXjsF2qt7o%253D&md5=bde723de92b56d7bbfbe2912ad5209b0Synthesis of Partially Modified Retro and Retroinverso ψ[NHCH(CF3)]-PeptidesVolonterio, Alessandro; Bravo, Pierfrancesco; Zanda, MatteoOrganic Letters (2000), 2 (13), 1827-1830CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)Asym. conjugate addns. of chiral α-amino esters to chiral 4-trifluoromethyl Michael-acceptors were exploited to prep. a small library of enantiomerically pure partially modified retropeptides having a ψ[NHCH(CF3)] unit as a possible mimic of the classical ψ(NHCO) retropeptide unit. Yields were nearly quant., and the stereoselectivity, which is controlled mainly by the N nucleophile, was progressively higher with increasing the steric bulk of the α-amino ester side-chain.
- 238Sani, M.; Volonterio, A.; Zanda, M. The trifluoroethylamine function as peptide bond replacement. ChemMedChem 2007, 2, 1693– 1700, DOI: 10.1002/cmdc.200700156[Crossref], [PubMed], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXltlWlt7c%253D&md5=f319f5ec15482837b159ae6776302717The trifluoroethylamine function as peptide bond replacementSani, Monica; Volonterio, Alessandro; Zanda, MatteoChemMedChem (2007), 2 (12), 1693-1700CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Synthesis of peptidomimetics contg. a stereogenic trifluoroethylamine group in place of the peptide bond is discussed. Peptidomimetics contg. the trifluoroethylamine group in place of amide group have been found to be highly potent and metabolically stable inhibitors of cathepsin K.
- 239Zanda, M. Trifluoromethyl group: an effective xenobiotic function for peptide backbone modification. New J. Chem. 2004, 28, 1401– 1411, DOI: 10.1039/b405955g[Crossref], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVGqur3P&md5=7f40c026008b7e521e5a8d47cdc6c36cTrifluoromethyl group: an effective xenobiotic function for peptide backbone modificationZanda, MatteoNew Journal of Chemistry (2004), 28 (12), 1401-1411CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)A review. Peptides modified with fluoroalkyl functions in key backbone positions have been scarcely studied so far. Thus, little is known about their synthesis, their structural and physico-chem. properties, and their biol. features. Interest in this field of research led to the development of stereocontrolled synthetic protocols, both in soln. and in the solid phase, for many different fluoroalkyl peptidomimetics, i.e., bis-trifluoromethyl (Tfm) analogs of Pepstatin A, which are nanomolar and selective inhibitors of the protozoal aspartyl protease Plasmepsin II; Tfm-malic peptidomimetics that are micromolar inhibitors of some matrix metalloproteinases; partially modified retro (PMR) and retro-inverso (PMRI) ψ[CH(CF3)NH] peptides with a strong proclivity to assume turn-like conformations; ψ[CH(CF3)NH] peptide mimics having a great potential as hybrids between natural peptides and hydrolytic transition state analogs; PMR peptides incorporating a trifluoroalanine surrogate. These novel classes of fluorinated peptide mimics are likely to represent just the tip of an iceberg formed by new peptidomimetic structures with unique biomedicinal and pharmaceutical properties.
- 240Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L. T.; Falgueyret, J. P.; Kimmel, D. B.; Lamontagne, S.; Leger, S.; LeRiche, T.; Li, C. S.; Masse, F.; McKay, D. J.; Nicoll-Griffith, D. A.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau, D.; Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Therien, M.; Truong, V. L.; Venuti, M. C.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 2008, 18, 923– 928, DOI: 10.1016/j.bmcl.2007.12.047[Crossref], [PubMed], [CAS], Google Scholar240https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFWktro%253D&md5=e432a420a3ec99c784117750b9bbeda8The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin KGauthier, Jacques Yves; Chauret, Nathalie; Cromlish, Wanda; Desmarais, Sylvie; Duong, Le T.; Falgueyret, Jean-Pierre; Kimmel, Donald B.; Lamontagne, Sonia; Leger, Serge; LeRiche, Tammy; Li, Chun Sing; Masse, Frederic; McKay, Daniel J.; Nicoll-Griffith, Deborah A.; Oballa, Renata M.; Palmer, James T.; Percival, M. David; Riendeau, Denis; Robichaud, Joel; Rodan, Gideon A.; Rodan, Sevgi B.; Seto, Carmai; Therien, Michel; Truong, Vouy-Linh; Venuti, Michael C.; Wesolowski, Gregg; Young, Robert N.; Zamboni, Robert; Black, W. CameronBioorganic & Medicinal Chemistry Letters (2008), 18 (3), 923-928CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclin. species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.
- 241Grabowskal, U.; Chambers, T. J.; Shiroo, M. Recent developments in cathepsin K inhibitor design. Curr. Opin. Drug Discovery Dev. 2005, 8, 619– 630[PubMed], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2MvovVGquw%253D%253D&md5=5ebd36480debe8b08eab9c536fc70470Recent developments in cathepsin K inhibitor designGrabowskal Urszula; Chambers Timothy J; Shiroo MasahiroCurrent opinion in drug discovery & development (2005), 8 (5), 619-30 ISSN:1367-6733.Cathepsin K is abundantly and selectively expressed in osteoclasts where it plays a critical role in bone degradation. Cathepsin K inhibitors are the first antiresorptive agents that prevent bone loss while allowing bone formation to continue, thereby enhancing the quality and ultimately the strength of bone. The development of cathepsin K inhibitors requires appropriate cell-based assays and animal models. Advances in reversible cathepsin K inhibitor design from January 2004 are reviewed herein.
- 242Falgueyret, J. P.; Desmarais, S.; Oballa, R.; Black, W. C.; Cromlish, W.; Khougaz, K.; Lamontagne, S.; Masse, F.; Riendeau, D.; Toulmond, S.; Percival, M. D. Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. J. Med. Chem. 2005, 48, 7535– 7543, DOI: 10.1021/jm0504961[ACS Full Text], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFKgsLbE&md5=9522026bb34984bc66b462b2e95fcbb0Lysosomotropism of Basic Cathepsin K Inhibitors Contributes to Increased Cellular Potencies against Off-Target Cathepsins and Reduced Functional SelectivityFalgueyret, Jean-Pierre; Desmarais, Sylvie; Oballa, Renata; Black, W. Cameron; Cromlish, Wanda; Khougaz, Karine; Lamontagne, Sonia; Masse, Frederic; Riendeau, Denis; Toulmond, Sylvie; Percival, M. DavidJournal of Medicinal Chemistry (2005), 48 (24), 7535-7543CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The lysosomal cysteine protease cathepsin K is a target for osteoporosis therapy. The aryl-piperazine-contg. cathepsin K inhibitor CRA-013783/L-006235 (1) displays greater than 4000-fold selectivity against the lysosomal/endosomal antitargets cathepsin B, L, and S. However, 1 and other aryl-piperazine-contg. analogs, including balicatib (10), are ∼10-100-fold more potent in cell-based enzyme occupancy assays than against each purified enzyme. This phenomenon arises from their basic, lipophilic nature, which results in lysosomal trapping. Consistent with its lysosomotropic nature, 1 accumulates in cells and in rat tissues of high lysosome content. In contrast, nonbasic aryl-morpholino-contg. analogs do not exhibit lysosomotropic properties. Increased off-target activities of basic cathepsin K inhibitors were obsd. in a cell-based cathepsin S antigen presentation assay. No potency increases of basic inhibitors in a functional cathepsin K bone resorption whole cell assay were detected. Therefore, basic cathepsin K inhibitors, such as 1, suffer from reduced functional selectivities compared to those predicted using purified enzyme assays.
- 243Li, C. S.; Deschenes, D.; Desmarais, S.; Falgueyret, J. P.; Gauthier, J. Y.; Kimmel, D. B.; Leger, S.; Masse, F.; McGrath, M. E.; McKay, D. J.; Percival, M. D.; Riendeau, D.; Rodan, S. B.; Therien, M.; Truong, V. L.; Wesolowski, G.; Zamboni, R.; Black, W. C. Identification of a potent and selective non-basic cathepsin K inhibitor. Bioorg. Med. Chem. Lett. 2006, 16, 1985– 1989, DOI: 10.1016/j.bmcl.2005.12.071[Crossref], [PubMed], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhvVyqs74%253D&md5=e63e471204893774e5a617993ed9be18Identification of a potent and selective non-basic cathepsin K inhibitorLi, Chun Sing; Deschenes, Denis; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Gauthier, Jacques Yves; Kimmel, Donald. B.; Leger, Serge; Masse, Frederic; McGrath, Mary E.; McKay, Daniel J.; Percival, M. David; Riendeau, Denis; Rodan, Sevgi B.; Therien, Michel; Truong, Vouy-Linh; Wesolowski, Gregg; Zamboni, Robert; Black, W. CameronBioorganic & Medicinal Chemistry Letters (2006), 16 (7), 1985-1989CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of L-873724 (I) as a potent and selective non-basic cathepsin K inhibitor. This compd. showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The vols. of distribution close to unity were consistent with this compd. not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.
- 244Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falgueyret, J. P.; Leger, S.; Li, C. S.; Masse, F.; McKay, D. J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou, N.; Zamboni, R. Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2005, 15, 4741– 4744, DOI: 10.1016/j.bmcl.2005.07.071[Crossref], [PubMed], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVanu7%252FE&md5=c2ffc9bde9fbee7bb432d3c2485cfc62Trifluoroethylamines as amide isosteres in inhibitors of cathepsin KBlack, W. Cameron; Bayly, Christopher I.; Davis, Dana E.; Desmarais, Sylvie; Falgueyret, Jean-Pierre; Leger, Serge; Li, Chun Sing; Masse, Frederic; McKay, Daniel J.; Palmer, James T.; Percival, M. David; Robichaud, Joel; Tsou, Nancy; Zamboni, RobertBioorganic & Medicinal Chemistry Letters (2005), 15 (21), 4741-4744CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The nonbasic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compds. are 10- to 20-fold more potent than the corresponding amide derivs. Compd. (I) is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.
- 245Mullard, A. Merck &Co. drops osteoporosis drug odanacatib. Nat. Rev. Drug Discovery 2016, 15, 669, DOI: 10.1038/nrd.2016.207[Crossref], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFymtL3M&md5=596d89f78b8396f0193a4ecfaf6b50bdMerck & Co. drops osteoporosis drug odanacatibMullard, AsherNature Reviews Drug Discovery (2016), 15 (10), 669CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A discussion of the osteoporosis drug odanacatib.
- 246Butler, C. R.; Ogilvie, K.; Martinez-Alsina, L.; Barreiro, G.; Beck, E. M.; Nolan, C. E.; Atchison, K.; Benvenuti, E.; Buzon, L.; Doran, S.; Gonzales, C.; Helal, C. J.; Hou, X.; Hsu, M. H.; Johnson, E. F.; Lapham, K.; Lanyon, L.; Parris, K.; O’Neill, B. T.; Riddell, D.; Robshaw, A.; Vajdos, F.; Brodney, M. A. Aminomethyl-derived beta secretase (BACE1) inhibitors: engaging Gly230 without an anilide functionality. J. Med. Chem. 2017, 60, 386– 402, DOI: 10.1021/acs.jmedchem.6b01451[ACS Full Text], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVWmsrzF&md5=d92838ac7f8a09921a560c3c9bb5d1afAminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide FunctionalityButler, Christopher R.; Ogilvie, Kevin; Martinez-Alsina, Luis; Barreiro, Gabriela; Beck, Elizabeth M.; Nolan, Charles E.; Atchison, Kevin; Benvenuti, Eric; Buzon, Leanne; Doran, Shawn; Gonzales, Cathleen; Helal, Christopher J.; Hou, Xinjun; Hsu, Mei-Hui; Johnson, Eric F.; Lapham, Kimberly; Lanyon, Lorraine; Parris, Kevin; O'Neill, Brian T.; Riddell, David; Robshaw, Ashley; Vajdos, Felix; Brodney, Michael A.Journal of Medicinal Chemistry (2017), 60 (1), 386-402CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and reveals a potential metabolic site leading to the formation of an aniline, a structural motif of potential safety concern. The authors report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogs with an excellent balance of ADME properties and potency, however potential drug-drug interactions (DDI) were predicted based on CYP2D6 affinities. Generation and anal. of key BACE1 and CYP2D6 crystal structures identified strategies to obviate the DDI liability, leading to compd. I which exhibits robust in vivo efficacy as a BACE1 inhibitor.
- 247Gaudette, F.; Raeppel, S.; Nguyen, H.; Beaulieu, N.; Beaulieu, C.; Dupont, I.; Macleod, A. R.; Besterman, J. M.; Vaisburg, A. Identification of potent and selective VEGFR receptor tyrosine kinase inhibitors having new amide isostere headgroups. Bioorg. Med. Chem. Lett. 2010, 20, 848– 852, DOI: 10.1016/j.bmcl.2009.12.099[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVGrurc%253D&md5=4ce25cdb55c553f33a7dab139ee0cc04Identification of potent and selective VEGFR receptor tyrosine kinase inhibitors having new amide isostere headgroupsGaudette, Frederic; Raeppel, Stephane; Nguyen, Hannah; Beaulieu, Normand; Beaulieu, Carole; Dupont, Isabelle; MacLeod, A. Robert; Besterman, Jeffrey M.; Vaisburg, ArkadiiBioorganic & Medicinal Chemistry Letters (2010), 20 (3), 848-852CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A novel series of malonamide-type dual VEGFR2/c-Met inhibitors in which one of the amide bonds was replaced by an amide isostere-a trifluoroethylamine unit, was designed, synthesized, and evaluated for their enzymic and cellular inhibition of VEGFR2 and c-Met enzymes. Optimization of these mol. entities resulted in identification of potent and selective inhibitors of VEGFR2 enzyme.
- 248Kim, K.; Kang, J.; Kim, S.; Choi, S.; Lim, S.; Im, C.; Yim, C. Synthesis and cytotoxicity of new aromatic ceramide analogs with alkylsulfonamido chains. Arch. Pharmacal Res. 2007, 30, 570– 580, DOI: 10.1007/BF02977651[Crossref], [PubMed], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXms1alsbg%253D&md5=0202cbb47f48f4032195837de3e193c8Synthesis and cytotoxicity of new aromatic ceramide analogs with alkylsulfonamido chainsKim, Kyoungwon; Kang, Joosung; Kim, Seungyong; Choi, Suhang; Lim, Sejin; Im, Chaeuk; Yim, ChulbuArchives of Pharmacal Research (2007), 30 (5), 570-580CODEN: APHRDQ; ISSN:0253-6269. (Pharmaceutical Society of Korea)A series of D-erythro ceramide analogs, N-(2S,3R,4E)-1, 3-dihydroxy-5-Ph-pent-4-en-2-yl alkyl sulfonamides, were synthesized and evaluated for their in vitro cytotoxic activities against five human tumor cell lines. The arom. sulfonamido ceramide analog I showed more potent cytotoxic activity than that of the B13, indicating that a sulfonamide group appears to serve as a bioisostere of an amide in drug design. Variations in the alkyl sulfonyl chain length significantly influenced the cytotoxic activity of the sulfonamido ceramide analogs, but the introduction of a para halogen on the Ph ring of arom. ceramide analogs had no affect on the activity.
- 249Donelson, J. L.; Hodges-Loaiza, H. B.; Henriksen, B. S.; Hrycyna, C. A.; Gibbs, R. A. Solid-phase synthesis of prenylcysteine analogs. J. Org. Chem. 2009, 74, 2975– 2981, DOI: 10.1021/jo8021692[ACS Full Text], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjs1Gmur4%253D&md5=74cd6ddac16572a9dcb67214e46e6fb5Solid-phase synthesis of prenylcysteine analogsDonelson, James L.; Hodges-Loaiza, Heather B.; Henriksen, Brian S.; Hrycyna, Christine A.; Gibbs, Richard A.Journal of Organic Chemistry (2009), 74 (8), 2975-2981CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Prenylcysteine derivs. are of interest for a variety of different biol. reasons, including probing the CaaX protein processing pathway. A solid-phase synthesis protocol for the prepn. of prenylcysteines using 2-chlorotrityl chloride resin as a solid support has been developed. A series of novel amide-modified farnesylcysteine analogs were synthesized in both high purity and yield under mild conditions. The farnesylcysteine analogs were evaluated using human isoprenylcysteine carboxyl methyltransferase as a biol. target, and several new inhibitors, one with significantly enhanced potency, were identified.
- 250Majmudar, J. D.; Hahne, K.; Hrycyna, C. A.; Gibbs, R. A. Probing the isoprenylcysteine carboxyl methyltransferase (Icmt) binding pocket: sulfonamide modified farnesyl cysteine (SMFC) analogs as Icmt inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 2616– 2620, DOI: 10.1016/j.bmcl.2011.01.078[Crossref], [PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXltFKisbs%253D&md5=6d6a7272c83c936d4d99b0b88b134dbbProbing the isoprenylcysteine carboxyl methyltransferase (Icmt) binding pocket: Sulfonamide modified farnesyl cysteine (SMFC) analogs as Icmt inhibitorsMajmudar, Jaimeen D.; Hahne, Kalub; Hrycyna, Christine A.; Gibbs, Richard A.Bioorganic & Medicinal Chemistry Letters (2011), 21 (9), 2616-2620CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Human isoprenylcysteine carboxyl methyltransferase (hIcmt) is a promising anticancer target as it is important for the post-translational modification of oncogenic Ras proteins. We herein report the synthesis and biochem. activity of 41 farnesyl-cysteine based analogs vs. hIcmt. We have demonstrated that the amide linkage of a hIcmt substrate can be replaced by a sulfonamide bond to achieve hIcmt inhibition. The most potent sulfonamide-modified farnesyl cysteine analog was 6ag with an IC50 of 8.8 ± 0.5 μM for hIcmt.
- 251Koehn, F. E.; Carter, G. T. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discovery 2005, 4, 206– 220, DOI: 10.1038/nrd1657[Crossref], [PubMed], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhslSnsrg%253D&md5=ce80052abaa76430220ee5981138053eThe evolving role of natural products in drug discoveryKoehn, Frank E.; Carter, Guy T.Nature Reviews Drug Discovery (2005), 4 (3), 206-220CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Natural products and their derivs. have historically been invaluable as a source of therapeutic agents. However, in the past decade, research into natural products in the pharmaceutical industry has declined, owing to issues such as the lack of compatibility of traditional natural-product ext. libraries with high-throughput screening. However, as discussed in this review, recent technol. advances that help to address these issues, coupled with unrealized expectations from current lead-generation strategies, have led to a renewed interest in natural products in drug discovery.
- 252Ferreira, A. K.; Tavares, M. T.; Pasqualoto, K. F.; de Azevedo, R. A.; Teixeira, S. F.; Ferreira-Junior, W. A.; Bertin, A. M.; de-Sa-Junior, P. L.; Barbuto, J. A.; Figueiredo, C. R.; Cury, Y.; Damiao, M. C.; Parise-Filho, R. RPF151, a novel capsaicin-like analogue: in vitro studies and in vivo preclinical antitumor evaluation in a breast cancer model. Tumor Biol. 2015, 36, 7251– 7267, DOI: 10.1007/s13277-015-3441-z[Crossref], [CAS], Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVyqs73E&md5=fb6c7a340e8127027f797fd16d425c69RPF151, a novel capsaicin-like analogue: in vitro studies and in vivo preclinical antitumor evaluation in a breast cancer modelFerreira, Adilson Kleber; Tavares, Mauricio Temotheo; Pasqualoto, Kerly Fernanda Mesquita; de Azevedo, Ricardo Alexandre; Teixeira, Sarah Fernandes; Ferreira-Junior, Wilson Alves; Bertin, Ariane Matiello; de-Sa-Junior, Paulo Luiz; Barbuto, Jose Alexandre Marzagao; Figueiredo, Carlos Rogerio; Cury, Yara; Damiao, Mariana Celestina Frojuello Costa Bernstorff; Parise-Filho, RobertoTumor Biology (2015), 36 (9), 7251-7267CODEN: TUMBEA; ISSN:1010-4283. (Springer)Capsaicin, the primary pungent component of the chili pepper, has antitumor activity. Herein, we describe the activity of RPF151, an alkyl sulfonamide analog of capsaicin, against MDA-MB-231 breast cancer cells. RPF151 was synthesized, and mol. modeling was used to compare capsaicin and RPF151. Cytotoxicity of RPF151 on MDA-MB-231 was also evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5diphenyltetrazolium bromide (MTT) assay. Cell cycle anal., by flow cytometry, and Western blot anal. of cycle-related proteins were used to evaluate the antiproliferative mechanisms. Apoptosis was evaluated by phosphatidyl-serine externalization, cleavage of Ac-YVAD-AMC, and Bcl-2 expression. The prodn. of reactive oxygen species was evaluated by flow cytometry. RPF151 in vivo antitumor effects were investigated in murine MDA-MB-231 model. This study shows that RPF151 downregulated p21 and cyclins A, D1, and D3, leading to S-phase arrest and apoptosis. Although RPF151 has induced the activation of TRPV-1 and TRAIL-R1/DR4 and TRAIL-2/DR5 on the surface of MDA-MB-231 cells, its in vivo antitumor activity was TRPV-1-independent, thus suggesting that RPF151 should not have the same pungency-based limitation of capsaicin. In silico anal. corroborated the biol. findings, showing that RPF151 has physicochem. improvements over capsaicin. Overall, the activity of RPF151 against MDA-MB-231 and its lower pungency suggest that it may have a relevant role in cancer therapy.
- 253de-Sa-Junior, P. L.; Pasqualoto, K. F.; Ferreira, A. K.; Tavares, M. T.; Damiao, M. C.; de Azevedo, R. A.; Camara, D. A.; Pereira, A.; de Souza, D. M.; Parise Filho, R. RPF101, a new capsaicin-like analogue, disrupts the microtubule network accompanied by arrest in the G2/M phase, inducing apoptosis and mitotic catastrophe in the MCF-7 breast cancer cells. Toxicol. Appl. Pharmacol. 2013, 266, 385– 398, DOI: 10.1016/j.taap.2012.11.029[Crossref], [PubMed], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXos1Sqsw%253D%253D&md5=d79537f1bb7ea7762db7f967731e5c67RPF101, a new capsaicin-like analogue, disrupts the microtubule network accompanied by arrest in the G2/M phase, inducing apoptosis and mitotic catastrophe in the MCF-7 breast cancer cellsde-Sa-Junior, Paulo Luiz; Pasqualoto, Kerly Fernanda Mesquita; Ferreira, Adilson Kleber; Tavares, Mauricio Temotheo; Damiao, Mariana Celestina Frojuello Costa Bernstorff; de Azevedo, Ricardo Alexandre; Camara, Diana Aparecida Dias; Pereira, Alexandre; Madeiro de Souza, Dener; Parise Filho, RobertoToxicology and Applied Pharmacology (2013), 266 (3), 385-398CODEN: TXAPA9; ISSN:0041-008X. (Elsevier Inc.)Breast cancer is the world's leading cause of death among women. This situation imposes an urgent development of more selective and less toxic agents. The use of natural mol. fingerprints as sources for new bioactive chem. entities has proven to be a quite promising and efficient method. Capsaicin, which is the primary pungent compd. in red peppers, was reported to selectively inhibit the growth of a variety tumor cell lines. Here, we report for the first time a novel synthetic capsaicin-like analog, RPF101, which presents a high antitumor activity on MCF-7 cell line, inducing arrest of the cell cycle at the G2/M phase through a disruption of the microtubule network. Furthermore, it causes cellular morphol. changes characteristic of apoptosis and a decrease of Δψm. Mol. modeling studies corroborated the biol. findings and suggested that RPF101, besides being a more reactive mol. towards its target, may also present a better pharmacokinetic profile than capsaicin. All these findings support the fact that RPF101 is a promising anticancer agent.
- 254Choy, N.; Choi, H.-I.; Jung, W. H.; Kim, C. R.; Yoon, H.; Kim, S. C.; Lee, T. G.; Koh, J. S. Synthesis of irreversible HIV-1 protease inhibitors containing sulfonamide and sulfone as amide bond isosteres. Bioorg. Med. Chem. Lett. 1997, 7, 2635– 2638, DOI: 10.1016/S0960-894X(97)10054-3[Crossref], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXnt1WktL8%253D&md5=426c15ab9072ba5c2499707c42e84127Synthesis of irreversible HIV-1 protease inhibitors containing sulfonamide and sulfone as amide bond isosteresChoy, Nakyen; Choi, Ho-il; Jung, Won Hee; Kim, Chung Ryeol; Yoon, Heungsik; Kim, Sung Chun; Lee, Tae Gyu; Koh, Jong SungBioorganic & Medicinal Chemistry Letters (1997), 7 (20), 2635-2638CODEN: BMCLE8; ISSN:0960-894X. (Elsevier)Novel irreversible HIV-1 protease inhibitors contg. sulfonamide and sulfone as amide bond isosteres were designed, synthesized, and kinetically characterized. A representative compd. (I) displayed rapid, time-dependent inactivation of HIV-1 protease and high potency in cell culture with IC50 of 6.6 nM.
- 255Shu, B.; Gong, P. Structural basis of viral RNA-dependent RNA polymerase catalysis and translocation. Proc. Natl. Acad. Sci. U. S. A. 2016, 113, E4005– E4014, DOI: 10.1073/pnas.1602591113[Crossref], [PubMed], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFentrnO&md5=c06d8ebd751beab84fd77603cb82000dStructural basis of viral RNA-dependent RNA polymerase catalysis and translocationShu, Bo; Gong, PengProceedings of the National Academy of Sciences of the United States of America (2016), 113 (28), E4005-E4014CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Viral RNA-dependent RNA polymerases (RdRPs) play essential roles in viral genome replication and transcription. We previously reported several structural states of the poliovirus RdRP nucleotide addn. cycle (NAC) that revealed a unique palm domain-based active site closure mechanism and proposed a six-state NAC model including a hypothetical state representing translocation intermediates. Using the RdRP from another human enterovirus, enterovirus 71, here we report seven RdRP elongation complex structures derived from a crystal lattice that allows three NAC events. These structures suggested a key order of events in initial NTP binding and NTP-induced active site closure and revealed a bona fide translocation intermediate featuring asym. movement of the template-product duplex. Our work provides essential missing links in understanding NTP recognition and translocation mechanisms in viral RdRPs and emphasizes the uniqueness of the viral RdRPs compared with other processive polymerases.
- 256Venkataraman, S.; Prasad, B.; Selvarajan, R. RNA dependent RNA Polymerases: insights from structure, function and evolution. Viruses 2018, 10, 76, DOI: 10.3390/v10020076[Crossref], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlOns7fM&md5=c319809dde32ed7bef696dd77566920dRNA dependent RNA polymerases: insights from structure, function and evolutionVenkataraman, Sangita; Prasad, Burra V. L. S.; Selvarajan, RamasamyViruses (2018), 10 (2), 76/1-76/23CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)RNA dependent RNA polymerase (RdRp) is one of the most versatile enzymes of RNA viruses that is indispensable for replicating the genome as well as for carrying out transcription. The core structural features of RdRps are conserved, despite the divergence in their sequences. The structure of RdRp resembles that of a cupped right hand and consists of fingers, palm and thumb subdomains. The catalysis involves the participation of conserved aspartates and divalent metal ions. Complexes of RdRps with substrates, inhibitors and metal ions provide a comprehensive view of their functional mechanism and offer valuable insights regarding the development of antivirals. In this article, we provide an overview of the structural aspects of RdRps and their complexes from the Group III, IV and V viruses and their structure-based phylogeny.
- 257Abdurakhmanov, E.; Oie Solbak, S.; Danielson, U. H. Biophysical mode-of-action and selectivity analysis of allosteric inhibitors of hepatitis C virus (HCV) polymerase. Viruses 2017, 9, 151, DOI: 10.3390/v9060151[Crossref], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVertbbF&md5=33824302ecfbe96c36b990b79d587e24Biophysical mode-of-action and selectivity analysis of allosteric inhibitors of hepatitis C virus (HCV) polymeraseAbdurakhmanov, Eldar; Solbak, Sara Oie; Danielson, U. HelenaViruses (2017), 9 (6), 151/1-151/20CODEN: VIRUBR; ISSN:1999-4915. (MDPI AG)Allosteric inhibitors of hepatitis C virus (HCV) non-structural protein 5B (NS5B) polymerase are effective for treatment of genotype 1, although their mode of action and potential to inhibit other isolates and genotypes are not well established. We have used biophys. techniques and a novel biosensor-based real-time polymerase assay to investigate the mode-of-action and selectivity of four inhibitors against enzyme from genotypes 1b (BK and Con1) and 3a. Two thumb inhibitors (lomibuvir and filibuvir) interacted with all three NS5B variants, although the affinities for the 3a enzyme were low. Of the two tested palm inhibitors (dasabuvir and nesbuvir), only dasabuvir interacted with the 1b variant, and nesbuvir interacted with NS5B 3a. Lomibuvir, filibuvir and dasabuvir stabilized the structure of the two 1b variants, but not the 3a enzyme. The thumb compds. interfered with the interaction between the enzyme and RNA and blocked the transition from initiation to elongation. The two allosteric inhibitor types have different inhibition mechanisms. Sequence and structure anal. revealed differences in the binding sites for 1b and 3a variants, explaining the poor effect against genotype 3a NS5B. The indirect mode-of-action needs to be considered when designing allosteric compds. The current approach provides an efficient strategy for identifying and optimizing allosteric inhibitors targeting HCV genotype 3a.
- 258Kati, W.; Koev, G.; Irvin, M.; Beyer, J.; Liu, Y.; Krishnan, P.; Reisch, T.; Mondal, R.; Wagner, R.; Molla, A.; Maring, C.; Collins, C. In vitro activity and resistance profile of dasabuvir, a nonnucleoside hepatitis C virus polymerase inhibitor. Antimicrob. Agents Chemother. 2015, 59, 1505– 1511, DOI: 10.1128/AAC.04619-14[Crossref], [PubMed], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtFais7Y%253D&md5=90e37367cb8769886a834675a9f237e9In Vitro Activity and resistance profile of dasabuvir, a nonnucleoside hepatitis C virus polymerase inhibitorKati, Warren; Koev, Gennadiy; Irvin, Michelle; Beyer, Jill; Liu, Yaya; Krishnan, Preethi; Reisch, Thomas; Mondal, Rubina; Wagner, Rolf; Molla, Akhteruzzaman; Maring, Clarence; Collins, ChristineAntimicrobial Agents and Chemotherapy (2015), 59 (3), 1505-1511/1-1505-1511/7, 7 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Dasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clin. isolates, with 50% inhibitory concn. (IC50) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concn. (EC50) values of 7.7 and 1.8 nM, resp., with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clin. isolates from treatment-naive patients, with EC50s ranging between 0.15 and 8.57 nM. Maintenance of replicon-contg. cells in medium contg. dasabuvir at concns. 10-fold or 100-fold greater than the EC50 resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections.
- 259Pierra Rouviere, C.; Amador, A.; Badaroux, E.; Convard, T.; Da Costa, D.; Dukhan, D.; Griffe, L.; Griffon, J. F.; LaColla, M.; Leroy, F.; Liuzzi, M.; Loi, A. G.; McCarville, J.; Mascia, V.; Milhau, J.; Onidi, L.; Paparin, J. L.; Rahali, R.; Sais, E.; Seifer, M.; Surleraux, D.; Standring, D.; Dousson, C. Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase. Bioorg. Med. Chem. Lett. 2016, 26, 4536– 4541, DOI: 10.1016/j.bmcl.2016.01.042[Crossref], [PubMed], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhtlalt7zL&md5=8249681b3bba0b04b03da0b11aada4a7Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerasePierra Rouviere, Claire; Amador, Agnes; Badaroux, Eric; Convard, Thierry; Da Costa, Daniel; Dukhan, David; Griffe, Ludovic; Griffon, Jean-Francois; La Colla, Massimiliano; Leroy, Frederic; Liuzzi, Michel; Loi, Anna Giulia; McCarville, Joe; Mascia, Valeria; Milhau, Julien; Onidi, Loredana; Paparin, Jean-Laurent; Rahali, Rachid; Sais, Efisio; Seifer, Maria; Surleraux, Dominique; Standring, David; Dousson, CyrilBioorganic & Medicinal Chemistry Letters (2016), 26 (18), 4536-4541CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equiv. in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by x-ray co-crystn. study.
- 260Rochon, K.; Proteau-Gagne, A.; Bourassa, P.; Nadon, J. F.; Cote, J.; Bournival, V.; Gobeil, F., Jr.; Guerin, B.; Dory, Y. L.; Gendron, L. Preparation and evaluation at the delta opioid receptor of a series of linear leu-enkephalin analogues obtained by systematic replacement of the amides. ACS Chem. Neurosci. 2013, 4, 1204– 1216, DOI: 10.1021/cn4000583[ACS Full Text], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntVCqu7s%253D&md5=8f417f41d4c48bd3aa3a4d4a52604ad4Preparation and Evaluation at the Delta Opioid Receptor of a Series of Linear Leu-Enkephalin Analogues Obtained by Systematic Replacement of the AmidesRochon, Kristina; Proteau-Gagne, Arnaud; Bourassa, Philippe; Nadon, Jean-Francois; Cote, Jerome; Bournival, Veronique; Gobeil, Fernand; Guerin, Brigitte; Dory, Yves L.; Gendron, LouisACS Chemical Neuroscience (2013), 4 (8), 1204-1216CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Leu-enkephalin analogs, in which the amide bonds were sequentially and systematically replaced either by ester or N-Me amide bonds, were prepd. using classical org. chem. as well as solid-phase peptide synthesis (SPPS). The peptidomimetics were characterized using competition binding, ERK1/2 phosphorylation, receptor internalization, and contractility assays to evaluate their pharmacol. profile over the delta opioid receptor (DOPr). The lipophilicity (LogD7.4) and plasma stability of the active analogs were also measured. The results here revealed that the last amide bond can be successfully replaced by either an ester or an N-Me amide bond without significantly decreasing the biol. activity of the corresponding analogs when compared to Leu-enkephalin. The peptidomimetics with an N-Me amide function between residues Phe and Leu were found to be more lipophilic and more stable than Leu-enkephalin. Findings from the present study further revealed that the hydrogen-bond donor properties of the fourth amide of Leu-enkephalin are not important for its biol. activity on DOPr. In addn., the results showed that the systematic replacement of amide bonds by isosteric functions represents an efficient way to design and synthesize novel peptide analogs with enhanced stability. In conclusion, the authors suggest that such a strategy can also be useful to study the biol. roles of amide bonds.
- 261Hann, M. M.; Sammes, P. G.; Kennewell, P. D.; Taylor, J. B. On double bond isosters of the peptide bond; an enkephalin analogue. J. Chem. Soc., Chem. Commun. 1980, 234– 235, DOI: 10.1039/c39800000234[Crossref], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXlsFSlsb0%253D&md5=7defca8db5fbe3f588428a99382b72aaOn double bond isosteres of the peptide bond; an enkephalin analogHann, Michael M.; Sammes, Peter G.; Kennewell, Peter D.; Taylor, John B.Journal of the Chemical Society, Chemical Communications (1980), (5), 234-5CODEN: JCCCAT; ISSN:0022-4936.A route to peptide analogs incorporating a trans C-C double bond in place of an amide bond is described and illustrated by the prepn. of leucine enkephalin analog I. The opiate activity of I was assessed; I had an IC50 of 600nM against [3H]naloxone bound to rat brain homogenates at 30°.
- 262Hann, M. M.; Sammes, P. G.; Kennewell, P. D.; Taylor, J. B. On the double bond isostere of the peptide bond: preparation of an enkephalin analogue. J. Chem. Soc., Perkin Trans. 1 1982, 307– 314, DOI: 10.1039/p19820000307[Crossref], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XksFKhs7c%253D&md5=f2e6ec3a9f39f4a8cc32de8d4a4fdc22On the double bond isostere of the peptide bond: preparation of an enkephalin analogHann, Michael M.; Sammes, Peter G.; Kennewell, Peter D.; Taylor, John B.Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1982), (1), 307-14CODEN: JCPRB4; ISSN:0300-922X.The prepn. is described of a dipeptide analog in which a C:C bond replaces the normal amide bond. Ether I (R = CHO), prepd. by redn. of I (R = CO2Me), underwent Wittig reaction with Ph3P+CH2C≡CSiMe3 Br- to give 76% I [R = (E)-CH:CHC≡CSiMe3], which underwent desilylation and oxidn. to give 75% I [R = (E)-CH:CHCH2CO2H] (II). II was condensed with H-Gly-Phe-Leu-OMe to give 68% I [R = (E)-CH:CHCH2CO-Gly-Phe-Leu-OMe], which was deprotected to give enkephalin analog III. III exhibited a biol. activity similar to that of enkephalin. The significance of the isosteric replacement of the amide group is discussed.
- 263Wipf, P.; Henninger, T. C.; Geib, S. J. Methyl- and (trifluoromethyl)alkene peptide isosteres: synthesis and evaluation of their potential as β-turn promoters and peptide mimetics. J. Org. Chem. 1998, 63, 6088– 6089, DOI: 10.1021/jo981057v[ACS Full Text], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXltFejsLg%253D&md5=a1d8b91ced24c2d1871dd041115a6b52Methyl- and (Trifluoromethyl)alkene Peptide Isosteres: Synthesis and Evaluation of Their Potential as β-Turn Promoters and Peptide MimeticsWipf, Peter; Henninger, Todd C.; Geib, Steven J.Journal of Organic Chemistry (1998), 63 (18), 6088-6089CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Enantioselective synthetic approaches were devised for L-ala-D-Ala (or enantiomeric) dipeptide alkene isostere sequences that, for the first time, included the prepn. of a (trifluoromethyl)alkene isostere. An X-ray study established that methyl- and trifluoromethyl-substituted alkenes provide conformationally considerably more highly preorganized backbone-rigidified peptide mimetics than the parent disubstituted alkenes.
- 264Donner, P.; Randolph, J. T.; Huang, P.; Wagner, R.; Maring, C.; Lim, B. H.; Colletti, L.; Liu, Y.; Mondal, R.; Beyer, J.; Koev, G.; Marsh, K.; Beno, D.; Longenecker, K.; Pilot-Matias, T.; Kati, W.; Molla, A.; Kempf, D. High potency improvements to weak aryl uracil HCV polymerase inhibitor leads. Bioorg. Med. Chem. Lett. 2013, 23, 4367– 4369, DOI: 10.1016/j.bmcl.2013.05.078[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXpslGjurk%253D&md5=5bd3f614d5644d6b2f8ff963c090e9b1High potency improvements to weak aryl uracil HCV polymerase inhibitor leadsDonner, Pamela; Randolph, John T.; Huang, Peggy; Wagner, Rolf; Maring, Clarence; Lim, Ben Hock; Colletti, Lynn; Liu, Yaya; Mondal, Rubina; Beyer, Jill; Koev, Gennadiy; Marsh, Kennan; Beno, David; Longenecker, Kenton; Pilot-Matias, Tami; Kati, Warren; Molla, Akhter; Kempf, DaleBioorganic & Medicinal Chemistry Letters (2013), 23 (15), 4367-4369CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Described herein is the development of a potent non-nucleoside, small mol. inhibitor of genotype 1 HCV NS5B Polymerase. A 23 μM inhibitor that was active against HCV polymerase was further elaborated into a potent single-digit nanomolar inhibitor of HCV NS5B polymerase by addnl. manipulation of the R and R1 substituents. Subsequent modifications to improve phys. properties were made to achieve an acceptable pharmacokinetic profile.
- 265Randolph, J. T.; Krueger, A. C.; Donner, P. L.; Pratt, J. K.; Liu, D.; Motter, C. E.; Rockway, T. W.; Tufano, M. D.; Wagner, R.; Lim, H. B.; Beyer, J. M.; Mondal, R.; Panchal, N. S.; Colletti, L.; Liu, Y.; Koev, G.; Kati, W. M.; Hernandez, L. E.; Beno, D. W. A.; Longenecker, K. L.; Stewart, K. D.; Dumas, E. O.; Molla, A.; Maring, C. J. Synthesis and biological characterization of aryl uracil inhibitors of hepatitis C virus NS5B polymerase: discovery of ABT-072, a trans-stilbene analog with good oral bioavailability. J. Med. Chem. 2018, 61, 1153– 1163, DOI: 10.1021/acs.jmedchem.7b01630[ACS Full Text], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1GgurY%253D&md5=e5fe750b61c6fc317eeae03d1bea8955Synthesis and Biological Characterization of Aryl Uracil Inhibitors of Hepatitis C Virus NS5B Polymerase: Discovery of ABT-072, a trans-Stilbene Analog with Good Oral BioavailabilityRandolph, John T.; Krueger, A. Chris; Donner, Pamela L.; Pratt, John K.; Liu, Dachun; Motter, Christopher E.; Rockway, Todd W.; Tufano, Michael D.; Wagner, Rolf; Lim, Hock B.; Beyer, Jill M.; Mondal, Rubina; Panchal, Neeta S.; Colletti, Lynn; Liu, Yaya; Koev, Gennadiy; Kati, Warren M.; Hernandez, Lisa E.; Beno, David W. A.; Longenecker, Kenton L.; Stewart, Kent D.; Dumas, Emily O.; Molla, Akhteruzzaman; Maring, Clarence J.Journal of Medicinal Chemistry (2018), 61 (3), 1153-1163CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compd. was identified during a medicinal chem. effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compd. permeability and soly. and provided much better pharmacokinetic properties in preclin. species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clin. studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clin. study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virol. response at 24 wk after dosing (SVR24) in 10 of 11 patients who received treatment.
- 266Durham, P. L. Calcitonin gene-related peptide (CGRP) and migraine. Headache 2006, 46 (Suppl. 1), S3– S8, DOI: 10.1111/j.1526-4610.2006.00483.x[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28rgtlKhsQ%253D%253D&md5=0336b66327b4a1b82d7ea5b0dff485bfCalcitonin gene-related peptide (CGRP) and migraineDurham Paul LHeadache (2006), 46 Suppl 1 (), S3-8 ISSN:0017-8748.The neuropeptide calcitonin gene-related peptide (CGRP) has long been postulated to play an integral role in the pathophysiology of migraine. While clinical findings are consistent with such a role, the specific pathogenic mechanisms of CGRP in migraine have remained speculative until recently. Through advances in molecular neuroscience, the pathogenic mechanisms of CGRP in migraine have begun to be elucidated. This paper discusses the hypothesized role of CGRP in migraine and reviews recent findings on the molecular mechanisms of this neuropeptide in migraine pathophysiology. Studies in cultured trigeminal neurons demonstrate that CGRP is released from trigeminal ganglia cells, that CGRP transcription is increased under conditions mimicking neurogenic inflammation, that migraine pharmacotherapies can both reduce CGRP release and inhibit CGRP transcription, and that tumor necrosis factor-alpha (TNF-alpha), an endogenous inflammatory mediator implicated in migraine, can stimulate CGRP transcription. Together, the results suggest that, in migraine, activation of trigeminal nerves release CGRP and other peptides that cause the release of proinflammatory mediators. These mediators further increase CGRP synthesis and release over hours to days in correspondence with the 4- to 72-hour duration of a typical migraine episode. The increased CGRP synthesis and release might be mediated by activation of mitogen-activated protein kinase pathways, which, in turn, can be modulated by endogenous inflammatory substances such as TNF-alpha and affected by drugs such as sumatriptan.
- 267Russell, F. A.; King, R.; Smillie, S. J.; Kodji, X.; Brain, S. D. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol. Rev. 2014, 94, 1099– 1142, DOI: 10.1152/physrev.00034.2013[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFansbnI&md5=dabce66d0b7604444f8366056f1ba2fdCalcitonin gene-related peptide: physiology and pathophysiologyRussell, F. A.; King, R.; Smillie, S.-J.; Kodji, X.; Brain, S. D.Physiological Reviews (2014), 94 (4), 1099-1142CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)A review. Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiol. and pathol. conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biol., but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this mol.
- 268Stump, C. A.; Bell, I. M.; Bednar, R. A.; Bruno, J. G.; Fay, J. F.; Gallicchio, S. N.; Johnston, V. K.; Moore, E. L.; Mosser, S. D.; Quigley, A. G.; Salvatore, C. A.; Theberge, C. R.; Blair Zartman, C.; Zhang, X. F.; Kane, S. A.; Graham, S. L.; Vacca, J. P.; Williams, T. M. The discovery of highly potent CGRP receptor antagonists. Bioorg. Med. Chem. Lett. 2009, 19, 214– 217, DOI: 10.1016/j.bmcl.2008.10.106[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlvFKk&md5=ad4ac18cac6f692017e08a3f3e946937The discovery of highly potent CGRP receptor antagonistsStump, Craig A.; Bell, Ian M.; Bednar, Rodney A.; Bruno, Joseph G.; Fay, John F.; Gallicchio, Steven N.; Johnston, Victor K.; Moore, Eric L.; Mosser, Scott D.; Quigley, Amy G.; Salvatore, Christopher A.; Theberge, Cory R.; Blair Zartman, C.; Zhang, Xu-Fang; Kane, Stefanie A.; Graham, Samuel L.; Vacca, Joseph P.; Williams, Theresa M.Bioorganic & Medicinal Chemistry Letters (2009), 19 (1), 214-217CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP Ki = 40 pM). The closely related compd. 27 demonstrated good oral bioavailability in dog and rhesus.
- 269Kim, J. J.; Wood, M. R.; Stachel, S. J.; de Leon, P.; Nomland, A.; Stump, C. A.; McWherter, M. A.; Schirripa, K. M.; Moore, E. L.; Salvatore, C. A.; Selnick, H. G. (E)-Alkenes as replacements of amide bonds: development of novel and potent acyclic CGRP receptor antagonists. Bioorg. Med. Chem. Lett. 2014, 24, 258– 261, DOI: 10.1016/j.bmcl.2013.11.027[Crossref], [PubMed], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFOku73O&md5=bc08abb6a057601a35feeb3e937b61df(E)-Alkenes as replacements of amide bonds: Development of novel and potent acyclic CGRP receptor antagonistsKim, June J.; Wood, Michael R.; Stachel, Shawn J.; de Leon, Pablo; Nomland, Ashley; Stump, Craig A.; McWherter, Melody A.; Schirripa, Kathy M.; Moore, Eric L.; Salvatore, Christopher A.; Selnick, Harold G.Bioorganic & Medicinal Chemistry Letters (2014), 24 (1), 258-261CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compds. against CGRP-R with low susceptibility to P-gp mediated efflux.
- 270Larsen, S. D.; Hester, M. R.; Craig Ruble, J.; Kamilar, G. M.; Romero, D. L.; Wakefield, B.; Melchior, E. P.; Sweeney, M. T.; Marotti, K. R. Discovery and initial development of a novel class of antibacterials: inhibitors of Staphylococcus aureus transcription/translation. Bioorg. Med. Chem. Lett. 2006, 16, 6173– 6177, DOI: 10.1016/j.bmcl.2006.09.044[Crossref], [PubMed], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtF2jsr%252FF&md5=e10c4cc122a0c2cd03d662ec57a9d77bDiscovery and initial development of a novel class of antibacterials: Inhibitors of Staphylococcus aureus transcription/translationLarsen, Scott D.; Hester, Matthew R.; Ruble, J. Craig; Kamilar, Gregg M.; Romero, Donna L.; Wakefield, Brian; Melchior, Earline P.; Sweeney, Michael T.; Marotti, Keith R.Bioorganic & Medicinal Chemistry Letters (2006), 16 (24), 6173-6177CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)The novel bacterial transcription/translation (TT) inhibitor 1 was identified through a combination of high throughput screening and exploratory medicinal chem. Initial optimization of the anthranilic acid moiety and sulfonamide amine diversity was accomplished via 1- and two-dimensional soln. phase libraries, resulting in an improvement in the MIC of the lead from 64 to 8 μg/mL (compd. 4l). Subsequent modification of the central arom. ring and further refinement of the sulfonamide amines required the development of a solid phase route on Wang resin. The resulting libraries generated a no. of potent antibacterials with MICs of ≤1 μg/mL (e.g., 10b, 12, and 13). During the course of this work, it became apparent that the antibacterial activity of the series is not fully correlated with TT inhibition, suggesting that at least one addnl. mechanism of action is operative.
- 271Brouwer, A. J.; Elgersma, R. C.; Jagodzinska, M.; Rijkers, D. T.; Liskamp, R. M. Delayed fibril formation of amylin(20-29) by incorporation of alkene dipeptidosulfonamide isosteres obtained by solid phase olefin cross metathesis. Bioorg. Med. Chem. Lett. 2008, 18, 78– 84, DOI: 10.1016/j.bmcl.2007.11.009[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXis1WntA%253D%253D&md5=9c6209f003e27d3a764ae1ab50d7f5afDelayed fibril formation of amylin(20-29) by incorporation of alkene dipeptidosulfonamide isosteres obtained by solid phase olefin cross metathesisBrouwer, Arwin J.; Elgersma, Ronald C.; Jagodzinska, Monika; Rijkers, Dirk T. S.; Liskamp, Rob M. J.Bioorganic & Medicinal Chemistry Letters (2008), 18 (1), 78-84CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)The synthesis of a new peptidomimetic structure, the alkene dipeptidosulfonamide isostere, is described. The synthesis is based on a cross metathesis reaction between two allylic building blocks, both in soln. and on the solid phase. This method was also applicable to the solid phase synthesis of alkene dipeptide isosteres. Derivs. of amylin(20-29) contg. the alkene dipeptidosulfonamide isostere as well as the alkene dipeptide isostere were successfully synthesized using the solid phase cross metathesis method. Investigation of relations between structure and fibril formation of these amylin(20-29) derivs. showed retardation of fibril formation and altered secondary structures, compared to native amylin(20-29).
- 272Yamamoto, Y.; Kimachi, T.; Kanaoka, Y.; Kato, S.; Bessho, K.; Matsumoto, T.; Kusakabe, T.; Sugiura, Y. Synthesis and DNA binding properties of amide bond-modified analogues related to distamycin. Tetrahedron Lett. 1996, 37, 7801– 7804, DOI: 10.1016/0040-4039(96)01782-0[Crossref], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xms1Wlt7s%253D&md5=de211ec74437e3ba757142a6502beaf0Synthesis and DNA binding properties of amide bond-modified analogs related to distamycinYamamoto, Yasuo; Kimachi, Tetsutaro; Kanaoka, Yoshitomo; Kato, Satoshi; Bessho, Kiyoshi; Matsumoto, Takuyuki; Kusakabe, Tetsuya; Sugiura, YukioTetrahedron Letters (1996), 37 (43), 7801-7804CODEN: TELEAY; ISSN:0040-4039. (Elsevier)Novel nitro analogs of distamycin I (X = CH:CH, COCO) which have a trans olefin bond or an α-diketo moiety instead of an amide bond were synthesized. Their DNA binding properties studied by ethidium displacement assay and MPE footprinting expts. were also described.
- 273Arcamone, F.; Penco, S.; Orezzi, P.; Nicolella, V.; Pirelli, A. Structure and synthesis of distamycin A. Nature 1964, 203, 1064– 1065, DOI: 10.1038/2031064a0[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2cXkvVClsrk%253D&md5=e418caf3c06330e1dec898811dbb7cf3Structure and synthesis of distamycin AArcamone, F.; Penco, S.; Orezzi, P.; Nicolella, V.; Pirelli, AnnamariaNature (London, United Kingdom) (1964), 203 (4949), 1064-5CODEN: NATUAS; ISSN:0028-0836.An amorphous product (fraction A) was sepd. from distamycin by solvent fractionation and column chromatography on Al2O3. The basic antibiotic distamycin A (I) was obtained as the HCl salt when 6N HCl was added to an aq. soln. of fraction A. By chem. and phys. methods I was identified as β-[1-methyl-4[1-methyl-4-(1-methyl-4-formylaminopyrrole-2-carboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine. The structure of I was also confirmed by synthesis.
- 274Wada, M.; Doi, R.; Hosotani, R.; Higashide, S.; Ibuka, T.; Habashita, H.; Nakai, K.; Fujii, N.; Imamura, M. Effect of a new bombesin receptor antagonist, (E)-alkene bombesin isostere, on amylase release from rat pancreatic acini. Pancreas 1995, 10, 301– 305, DOI: 10.1097/00006676-199504000-00013[Crossref], [PubMed], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2MzltVWgtw%253D%253D&md5=17c58c008d4217538db88e560d997920Effect of a new bombesin receptor antagonist, (E)-alkene bombesin isostere, on amylase release from rat pancreatic aciniWada M; Doi R; Hosotani R; Higashide S; Ibuka T; Habashita H; Nakai K; Fujii N; Imamura MPancreas (1995), 10 (3), 301-5 ISSN:0885-3177.The short-chain pseudopeptide, [D-Phe6, Leu13 psi (CH2NH)Leu14]bombesin(6-14) (RDI), is reported to be a potent antagonist of bombesin, and development of this type of compound has greatly contributed to the investigation of biological actions of bombesin and its related peptides. We recently synthesized (E)-alkene bombesin isostere by replacing the peptide bond with an (E)-double bond: [D-Phe6, Leu13 psi [(E)CH = CH]Leu14] bombesin(6-14) (EABI). The present study examined the effect of EABI on amylase release from rat pancreatic acini. EABI showed no agonistic activity at concentrations up to 1 microM, and RBI showed slight agonistic activity at concentrations > 10 nM. EABI caused a dose-dependent inhibition of amylase release stimulated by 0.1 nM bombesin, with an IC50 of 6.7 +/- 1.7 nM, and induced almost-complete inhibition at 0.3 microM. RDI caused a dose-dependent inhibition of amylase release, with an IC50 of 68.7 +/- 16 nM. EABI caused a parallel and rightward shift of the entire dose-response curve of bombesin-stimulated amylase release, and the degree of the shift was dependent on the concentrations of EABI. EABI (100 nM) and RDI (100 nM) inhibited amylase releases stimulated by gastrin-releasing peptide (1 nM) and neuromedin-C (1 nM). In contrast, amylase release stimulated by cholecystokinin octapeptide (0.1 nM), carbachol (10 microM), vasoactive intestinal peptide (1 nM), and gastrin-17 (10 nM) was not inhibited by EABI and RDI. The results indicate that EABI is a potent and specific bombesin receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
- 275Mishra, C. B.; Gusain, S.; Shalini, S.; Kumari, S.; Prakash, A.; Kumari, N.; Yadav, A. K.; Kumari, J.; Kumar, K.; Tiwari, M. Development of novel carbazole derivatives with effective multifunctional action against Alzheimer’s diseases: design, synthesis, in silico, in vitro and in vivo investigation. Bioorg. Chem. 2020, 95, 103524, DOI: 10.1016/j.bioorg.2019.103524[Crossref], [PubMed], [CAS], Google Scholar275https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFeqtb8%253D&md5=89b85d7b09dfa362d87b00574b30289eDevelopment of novel carbazole derivatives with effective multifunctional action against Alzheimer's diseases: Design, synthesis, in silico, in vitro and in vivo investigationMishra, Chandra Bhushan; Gusain, Siddharth; Shalini, Shruti; Kumari, Shikha; Prakash, Amresh; Kumari, Namrata; Yadav, Anita Kumari; Kumari, Jyoti; Kumar, Kundan; Tiwari, ManishaBioorganic Chemistry (2020), 95 (), 103524CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)Carbazole based novel multifunctional agents has been rationally designed and synthesized as potential anti-Alzheimer agents. Multi-functional activity of these derivs. have been assessed by performing various in-vitro assays and these compds. appeared to be potent AChE inhibitors, Aβ aggregation inhibitors, anti-oxidant and neuroprotective agents. Among the entire series, MT-1 and MT-6 were most potent multifunctional agents which displayed effective and selective AChE inhibition, Aβ disaggregation, anti-oxidant and metal chelation action. Neuroprotective activity of MT-6 has been examd. against H2O2 induced toxicity in SHSY-5Y cells and they have shown effective neuroprotection. Addnl., MT-6 did not display any significant toxicity in SHSY-5Y cells, indicating its non-toxic nature. Mol. docking and MD simulation studies have been also performed to explore mol. level interaction with AChE and Aβ. Finally, MT-6 was evaluated against scopolamine induced dementia model of mice and this compd. actively improved memory deficit and cognition impairment in scopolamine treated mice. Thus, novel carbazole deriv. MT-6 has been explored as an effective and safe multifunctional agent against AD and this mol. may be used as a suitable lead for development of effective anti-Alzheimer agents in future.
- 276Mishra, C. B.; Kumari, S.; Manral, A.; Prakash, A.; Saini, V.; Lynn, A. M.; Tiwari, M. Design, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer’s disease. Eur. J. Med. Chem. 2017, 125, 736– 750, DOI: 10.1016/j.ejmech.2016.09.057[Crossref], [PubMed], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1Clsb7J&md5=a0fb77041f4b505ed678700ac9a5a97aDesign, synthesis, in-silico and biological evaluation of novel donepezil derivatives as multi-target-directed ligands for the treatment of Alzheimer's diseaseMishra, Chandra Bhushan; Kumari, Shikha; Manral, Apra; Prakash, Amresh; Saini, Vikas; Lynn, Andrew M.; Tiwari, ManishaEuropean Journal of Medicinal Chemistry (2017), 125 (), 736-750CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A novel series of donepezil based multi-functional agents (E)-dimethoxy-((substituted piperazinyl)benzylidene)-dihydro-indenones I [R = Ph, 2-pyridyl, C(O)-(2-furyl), etc.] was designed and synthesized as potential anti-Alzheimer's agents. In-vitro studies revealed that these compds. demonstrated moderate to good AChE and Aβ aggregation inhibitory activity. These derivs. were also endowed with admirable antioxidant activity. Among the entire series compds. I [R = CH(4-FC6H4)2, 2-pyridyl, C(O)-(2-furyl)] appeared as most active multi-functional agents and displayed marked AChE inhibitory, Aβ disaggregation and antioxidant activity. Studies indicated that I [R = 2-pyridyl, C(O)-(2-furyl)] showed better AChE inhibitory activity than the std. drug donepezil and I [R = CH(4-FC6H4)2, 2-pyridyl, C(O)-(2-furyl)] exhibited better Aβ aggregation inhibitory activity than curcumin. These compds. successfully diminished H2O2 induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2 as well as Aβ induced toxicity in SH-SY5Y cells in a concn. dependent manner. Moreover, these derivs. did not exerted any significant toxicity in neuronal SH-SY5Y cells in cytotoxicity assay. To elucidate the plausible binding mode of these compds., mol. docking studies and mol. dynamics (MD) simulation studies were also performed and the results indicated their significant interactions with the active sites of AChE as well as Aβ1-42 peptide. Thus, the present study evidently showed that, the most active compds. were potent multi-functional agents against Alzheimer's disease and might serve as promising lead candidates for anti-Alzheimer drug development.
- 277Mishra, C. B.; Manral, A.; Kumari, S.; Saini, V.; Tiwari, M. Design, synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition, anti-β-amyloid aggregation, antioxidant and neuroprotection properties against Alzheimer’s disease. Bioorg. Med. Chem. 2016, 24, 3829– 3841, DOI: 10.1016/j.bmc.2016.06.027[Crossref], [PubMed], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVKnt7bN&md5=a77f2e5c5a6d642a703bf41c1735d421Design, synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition, anti-β-amyloid aggregation, antioxidant and neuroprotection properties against Alzheimer's diseaseMishra, Chandra Bhushan; Manral, Apra; Kumari, Shikha; Saini, Vikas; Tiwari, ManishaBioorganic & Medicinal Chemistry (2016), 24 (16), 3829-3841CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)-1H-indene-1,3(2H)-diones were designed, synthesized and appraised as multifunctional anti-Alzheimer agents. In vitro studies of compds. 27-38 showed that these compds. exhibit moderate to excellent AChE, BuChE and Aβ aggregation inhibitory activity. Notably, compds. 34 and 38 appeared as most active multifunctional agents in the entire series and exhibited excellent inhibition against AChE (IC50 = 0.048 μM: 34; 0.036 μM: 38), Aβ aggregation (max% inhibition 82.2%, IC50 = 9.2 μM: 34; max% inhibition 80.9%, IC50 = 10.11 μM: 38) and displayed significant antioxidant potential in ORAC-FL assay. Both compds. also successfully diminished H2O2 induced oxidative stress in SH-SY5Y cells. Fascinatingly, compds. 34 and 38 showed admirable neuroprotective effects against H2O2 and Aβ induced toxicity in SH-SY5Y cells. Addnl., both derivs. showed no considerable toxicity in neuronal cell viability assay and represented drug likeness properties in the primarily pharmacokinetics study. All these results together, propelled out that compds. 34 and 38 might serve as promising multi-functional lead candidates for treatment of AD in the future.
- 278Fu, Y.; Bieschke, J.; Kelly, J. W. E-olefin dipeptide isostere incorporation into a polypeptide backbone enables hydrogen bond perturbation: probing the requirements for Alzheimer’s amyloidogenesis. J. Am. Chem. Soc. 2005, 127, 15366– 15367, DOI: 10.1021/ja0551382[ACS Full Text], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFahsbbK&md5=3c322f177ef34107a06835b91c936ef3E-Olefin Dipeptide Isostere Incorporation into a Polypeptide Backbone Enables Hydrogen Bond Perturbation: Probing the Requirements for Alzheimer's AmyloidogenesisFu, Yanwen; Bieschke, Jan; Kelly, Jeffery W.Journal of the American Chemical Society (2005), 127 (44), 15366-15367CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The authors report the stereospecific synthesis of an E-olefin dipeptide (2R,3E,5S)-isostere, BocNHCH(CH2Ph)CH:CHCH(CH2Ph)CO2H, that can be used to make gram quantities of the Phe-Phe isostere desired for eliminating a specific backbone H-bond donor and acceptor in the Alzheimer's disease related Aβ peptide. The Aβ(1-40) peptide contg. the E-olefin isostere in place of Phe19-Phe20 was prepd. by solid-phase peptide synthesis and was subjected to amyloidogenesis conditions. This Aβ(1-40) peptide analog can aggregate into spherical morphologies but does not progress on to form protofibrils or fibrils as is the case for the all-amide sequence, providing insight into the structural requirements for amyloidogenesis.
- 279Shue, Y. K.; Tufano, M. D.; Carrera, G. M., Jr.; Kopecka, H.; Kuyper, S. L.; Holladay, M. W.; Lin, C. W.; Witte, D. G.; Miller, T. R.; Stashko, M.; Nadzan, A. M. Double bond isosteres of the peptide bond: synthesis and biological activity of cholecystokinin (CCK) C-terminal hexapeptide analogs. Bioorg. Med. Chem. 1993, 1, 161– 171, DOI: 10.1016/S0968-0896(00)82117-3[Crossref], [PubMed], [CAS], Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXhsFeqs78%253D&md5=2490ba46a4540221edce7cfe7a9be7f7Double bond isosteres of the peptide bond: synthesis and biological activity of cholecystokinin (CCK) C-terminal hexapeptide analogsShue, Youe Kong; Tufano, Michael D.; Carrera, George M., Jr.; Kopecka, Hana; Kuyper, Sharon L.; Holladay, Mark W.; Lin, Chun Wel; Witte, David G.; Miller, Thomas R.; et al.Bioorganic & Medicinal Chemistry (1993), 1 (3), 161-71CODEN: BMECEP; ISSN:0968-0896.New and existing methodologies were used to prep. a series of modified CCK analogs in which each amide bond was replaced by a trans-alkene unit. The data indicate that every amide linkage at C-terminal tetrapeptide (CCK-4) region is crucial for biol. activity. The amide bond beyond the Trp residue in the N-terminus can be replaced by a trans-alkene without affecting most of the binding potency and functional activity.
- 280Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 2018, 61, 5822– 5880, DOI: 10.1021/acs.jmedchem.7b01788[ACS Full Text], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2qu7w%253D&md5=2d0ce3326c7ff932da8d7d26972ced14Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug DesignMeanwell, Nicholas A.Journal of Medicinal Chemistry (2018), 61 (14), 5822-5880CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the Me group while also acting as a functional mimetic of the carbonyl, carbinol, andnitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metab., membrane permeability, and P-gp recognition of a mol. and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated mol. construction that broadens biol. mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a mol. are summarized.
- 281Pasternak, G. W.; Pan, Y. X. Mu opioids and their receptors: evolution of a concept. Pharmacol. Rev. 2013, 65, 1257– 1317, DOI: 10.1124/pr.112.007138[Crossref], [PubMed], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvV2rtLzJ&md5=49f6dc7f031f9302b72710d42f2a00eaMu opioids and their receptors: evolution of a conceptPasternak, Gavril W.; Pan, Ying-XianPharmacological Reviews (2013), 65 (4), 1257-1317CODEN: PAREAQ; ISSN:1521-0081. (American Society for Pharmacology and Experimental Therapeutics)A review. Opiates arc among the oldest medications available to manage a no. of medical problems. Although pain is the current focus, early use initially focused upon the treatment of dysentery. Opium contains high concns. of both morphine and codeine, along with thebaine, which is used in the synthesis of a no. of semisynthetic opioid analgesics. Thus, it is not surprising that new agents were initially based upon the morphine scaffold. The concept of multiple opioid receptors was first suggested almost 50 years ago, opening the possibility of new classes of drugs, but the morphine-like agents have remained the mainstay in the medical management of pain. Termed mu, our understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years. Early pharmacol. studies identified three major classes of receptors, helped by the discovery of endogenous opioid peptides and receptor subtypes-primarily through the synthesis of novel agents. These chem. biol. approaches were then eclipsed by the mol. biol. revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated.
- 282Weinberger, S. B.; Martinez, J. L., Jr. Characterization of hydrolysis of [leu]enkephalin and D-ala2-[L-leu]enkephalin in rat plasma. J. Pharmacol. Exp. Ther. 1988, 247, 129– 135[PubMed], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXmt1artLg%253D&md5=a79b38ac0b0767259539514956d97377Characterization of hydrolysis of [Leu]enkephalin and D-Ala2-[L-Leu]enkephalin in rat plasmaWeinberger, Susan B.; Martinez, Joe L., Jr.Journal of Pharmacology and Experimental Therapeutics (1988), 247 (1), 129-35CODEN: JPETAB; ISSN:0022-3565.Based on differences in total metabolite accumulation in the presence or absence of selective peptidase inhibitors, rat plasma is found to have its own unique pattern of enkephalin hydrolysis. Approx. 85-90% of the hydrolysis of [Leu5]enkephalin is attributed to the combined action of aminopeptidase M and angiotensin-converting enzyme, whereas enkephalinase and aminopeptidase MII activity against [Leu5]enkephalin are not detectable. Similarly, 80-90% of the hydrolysis of D-Ala2-[L-Leu5]enkephalin (DALLE) is due to the combined action of aminopeptidase M and angiotensin-converting enzyme, whereas aminopeptidase MII and enkephalinase activity against this substrate also could not be detected. This is in contrast to the high susceptibility to hydrolysis by enkephalinase, and the low susceptibility to aminopeptidase activity, for DALLE in brain tissue. Among other alternatives, it is suggested that enkephalin hydrolysis in plasma may appear to be unique because of differences in enzyme conformation and(or) the availability of a substance(s) that competes with, or alters the binding of, [Leu5]enkephalin, DALLE, or the inhibitors to the enzymes.
- 283Thompson, S. E.; Audus, K. L. Leucine-enkephalin metabolism in brain microvessel endothelial cells. Peptides 1994, 15, 109– 116, DOI: 10.1016/0196-9781(94)90178-3[Crossref], [PubMed], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXhvVens7c%253D&md5=aa361d0a0cd198493a8f83a09c4275afLeucine-enkephalin metabolism in brain microvessel endothelial cellsThompson, Suzanne E.; Audus, Kenneth L.Peptides (New York, NY, United States) (1994), 15 (1), 109-16CODEN: PPTDD5; ISSN:0196-9781.The metab. of leucine-enkephalin (LE) was investigated in primary cultures of bovine brain microvessel endothelial cell (BMEC) monolayers. LE was hydrolyzed slowly with < 40% of the peptide metabolized following a 5-h incubation with intact BMEC monolayers at 37°. Following sepn. and extn. of BMEC enzymes into cytosolic and membrane-bound fractions, LE was obsd. to be labile in the presence of both cytosolic and membrane-assocd. enzymes. A much greater concn. of enkephalin-hydrolyzing enzyme was assocd. with the cytosolic fraction. Resulting metabolite profiles for LE appeared to be the result of interactions of the peptide with primarily aminopeptidases and angiotensin-converting enzyme. Apparently, extensive metab. of LE solely by BMECs in the cerebrovasculature would require internalization by the cells and presentation to cytosolic enzymes.
- 284Karad, S. N.; Pal, M.; Crowley, R. S.; Prisinzano, T. E.; Altman, R. A. Synthesis and opioid activity of Tyr1-ψ[(Z)CF=CH]-Gly2 and Tyr1-ψ[(S)/(R)-CF3CH-NH]-Gly2 leu-enkephalin fluorinated peptidomimetics. ChemMedChem 2017, 12, 571– 576, DOI: 10.1002/cmdc.201700103[Crossref], [PubMed], [CAS], Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlsFOhtrk%253D&md5=dd84cc96cffca016898836a47604d917Synthesis and opioid activity of Tyr1-ψ[(Z)CF=CH]-Gly2 and Tyr1-ψ[(S)/(R)-CF3CH-NH]-Gly2 Leu-enkephalin fluorinated peptidomimeticsKarad, Somnath Narayan; Pal, Mohan; Crowley, Rachel S.; Prisinzano, Thomas E.; Altman, Ryan A.ChemMedChem (2017), 12 (8), 571-576CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr1-ψ[(Z)CF=CH]-Gly2) and trifluoroethylamine (Tyr1-ψ[(S)/(R)-CF3CH-NH]-Gly2) analogs of the endogenous opioid neuropeptide, Leu-enkephalin. The fluoroalkene peptidomimetic exhibited low nanomolar functional activity (5.0±2 nM and 60±15 nM for δ- and μ-opioid receptors, resp.) with a μ/δ-selectivity ratio that mimics that of the natural peptide. However, the trifluoroethylamine peptidomimetics, irresp. of stereochem., did not activate the opioid receptors, which suggest that bulky CF3 substituents are not tolerated at this position.
- 285Altman, R. A.; Sharma, K. K.; Rajewski, L. G.; Toren, P. C.; Baltezor, M. J.; Pal, M.; Karad, S. N. Tyr1- ψ[( Z)CF=CH]-Gly2 fluorinated peptidomimetic improves distribution and metabolism properties of leu-enkephalin. ACS Chem. Neurosci. 2018, 9, 1735– 1742, DOI: 10.1021/acschemneuro.8b00085[ACS Full Text], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnsVGgt7Y%253D&md5=e2b298070c410d9e7455c2a6bc236c6fTyr1-ψ[(Z)CF=CH]-Gly2 fluorinated peptidomimetics improves distribution and metabolism properties of Leu-enkephalinAltman, Ryan A.; Sharma, Krishna K.; Rajewski, Lian G.; Toren, Paul C.; Baltezor, Michael J.; Pal, Mohan; Karad, Somnath N.ACS Chemical Neuroscience (2018), 9 (7), 1735-1742CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Opioid peptides are key regulators in cellular and intercellular physiol. responses, and could be therapeutically useful for modulating several pathol. conditions. Unfortunately, the use of peptide-based agonists to target centrally located opioid receptors is limited by poor physicochem. (PC), distribution, metabolic, and pharmacokinetic (DMPK) properties that restrict penetration across the blood-brain barrier via passive diffusion. To address these problems, the present paper exploits fluorinated peptidomimetics to simultaneously modify PC and DMPK properties, thus facilitating entry into the central nervous system. As an initial example, the present paper exploited the Tyr1-ψ[(Z)CF=CH]-Gly2 peptidomimetic to improve PC druglike characteristics (computational), plasma and microsomal degrdn., and systemic and CNS distribution of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). Thus, the fluoroalkene replacement transformed an instable in vitro tool compd. into a stable and centrally distributed in vivo probe. In contrast, the Tyr1-ψ[CF3CH2-NH]-Gly2 peptidomimetic decreased stability by accelerating proteolysis at the Gly3-Phe4 position.
- 286Nadon, J. F.; Rochon, K.; Grastilleur, S.; Langlois, G.; Dao, T. T.; Blais, V.; Guerin, B.; Gendron, L.; Dory, Y. L. Synthesis of Gly-ψ[(Z)CF=CH]-Phe, a fluoroalkene dipeptide isostere, and its incorporation into a leu-enkephalin peptidomimetic. ACS Chem. Neurosci. 2017, 8, 40– 49, DOI: 10.1021/acschemneuro.6b00163[ACS Full Text], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslSisLnI&md5=893e2b2d560b04eebac0139a6830c42bSynthesis of Gly-ψ[(Z)CF=CH]-Phe, a fluoroalkene dipeptide isostere, and its incorporation into a Leu-enkephalin peptidomimeticNadon, Jean-Francois; Rochon, Kristina; Grastilleur, Sebastien; Langlois, Guillaume; Dao, Thi Thanh Ha; Blais, Veronique; Guerin, Brigitte; Gendron, Louis; Dory, Yves L.ACS Chemical Neuroscience (2017), 8 (1), 40-49CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)A new Leu-enkephalin peptidomimetic designed to explore the hydrogen bond acceptor ability of the third peptide bond has been prepd. and studied. This new analog is produced by replacing the third amide of Leu-enkephalin with a fluoroalkene. An efficient and innovative synthesis of the corresponding dipeptide surrogate Fmoc-Gly-ψ[(Z)CF=CH]-Phe-OH is described. The key step involves the alkylation of a tin dienolate from the less hindered face of its chiral sulfonamide auxiliary derived from camphor. Once its synthesis was complete, its incorporation into the peptidomimetic sequence was achieved on a solid support with chlorotrityl resin following the Fmoc (Fmoc = 9-fluorenylmethoxycarbonyl) strategy. The peptidomimetic was characterized using competition binding with [125I]-deltorphin I on membrane exts. of HEK293 cells expressing the mouse delta opioid receptor (DOPr) and based on its abilities to inhibit the elec. induced contractions of the mouse vas deferens and to activate the ERK1/2 signaling pathway in DRGF11/DOPr-GFP cells. Together with our previous observations, our findings strongly suggest that the third amide bond of Leu-enkephalin primarily acts as a hydrogen bond acceptor in DOPr. Consequently, this amide bond can be successfully replaced by an ester, a thioamide, or a fluoroalkene without greatly impacting the binding or biol. activity of the corresponding analogs. The lipophilicity (LogD7.4) of the active analog was also measured. It appears that fluoroalkenes are almost as efficient at increasing the lipophilicity as normal alkenes.
- 287Lajoie, G.; Lepine, F.; Lemaire, S.; Jolicoeur, F.; Aube, C.; Turcotte, A.; Belleau, B. Synthesis and biological activity of monothionated analogs of leucine-enkephalin. Int. J. Pept. Protein Res. 1984, 24, 316– 327, DOI: 10.1111/j.1399-3011.1984.tb00959.x[Crossref], [PubMed], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXps1Smsg%253D%253D&md5=995c8b138036a4879c0176ebeb283fb3Synthesis and biological activity of monothionated analogs of leucine-enkephalinLajoie, Gilles; Lepine, Francois; Lemaire, Simon; Jolicoeur, Francois; Aube, Carl; Turcotte, Andree; Belleau, BernardInternational Journal of Peptide & Protein Research (1984), 24 (4), 316-27CODEN: IJPPC3; ISSN:0367-8377.Title analogs H-DL-Tyr(S)-Gly-Gly-Phe-Leu-OH (I), H-Tyr-Gly(S)-Gly-Phe-Leu-OH (II), H-Tyr-Gly-Gly(S)-Phe-Leu-OH (III), and H-Tyr-Gly-Gly-Phe(S)-Leu-OH (IV) were prepd. and their opiate-like and analgesic activities were detd. Thus, Boc-Tyr(Boc)-NHMe (Boc = Me3CO2C) was thionated by 2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiophosphetane 2,4-disulfite to give Boc-Tyr(Boc)(S)-NHMe, which was S-methylated with MeI to give p-(BocO)C6H4CH2CH(NHBoc)C(SMe):NMe.HI, which was treated with H2S to give Boc-Tyr(Boc)(S)-SMe (V). Boc-Gly-Gly-Phe-Leu-OMe was Boc-deblocked and then coupled with V to give Boc-DL-Tyr(Boc)(S)-Gly-Gly-Phe-Leu-OMe, which was Boc-deblocked to give I. The biol. activities of I-IV depend on the backbone position of the thioamide function. The results are interpreted in terms of the thioamide function in receptor recognition processes, the probable behavior of thiopeptides toward physiol. relevant peptidases, and the structural divergences between tissue-sp. receptors.
- 288Proteau-Gagne, A.; Bournival, V.; Rochon, K.; Dory, Y. L.; Gendron, L. Exploring the backbone of enkephalins to adjust their pharmacological profile for the δ-opioid receptor. ACS Chem. Neurosci. 2010, 1, 757– 769, DOI: 10.1021/cn1000759[ACS Full Text], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFOis7jL&md5=b7e950764170a6b0482a75122b2b705fExploring the Backbone of Enkephalins To Adjust Their Pharmacological Profile for the δ-Opioid ReceptorProteau-Gagne, Arnaud; Bournival, Veronique; Rochon, Kristina; Dory, Yves L.; Gendron, LouisACS Chemical Neuroscience (2010), 1 (11), 757-769CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)The role of each of the four amide bonds in Leu5-enkephalin was investigated by systematically and sequentially replacing each with its corresponding trans-alkene. Six Leu5-enkephalin analogs based on six dipeptide surrogates and two Met5-enkephalin analogs were synthesized and thoroughly tested using a δ-opioid receptor internalization assay, an ERK1/2 activation assay, and a competition binding assay to evaluate their biol. properties. We obsd. that an E-alkene can efficiently replace the first amide bond of Leu5- and Met5-enkephalin without significantly affecting biol. activity. By contrast, the second amide bond was found to be highly sensitive to the same modification, suggesting that it is involved in biol. essential intra- or intermol. interactions. Finally, we obsd. that the affinity and activity of analogs contg. an E-alkene at either the third or fourth position were partially reduced, indicating that these amide bonds are less important for these intra- or intermol. interactions. Overall, our study demonstrates that the systematic and sequential replacement of amide bonds by E-alkene represents an efficient way to explore peptide backbones.
- 289Lee, C.; Ma, H.; Hang, J. Q.; Leveque, V.; Sklan, E. H.; Elazar, M.; Klumpp, K.; Glenn, J. S. The hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral protein. Virology 2011, 414, 10– 18, DOI: 10.1016/j.virol.2011.03.026[Crossref], [PubMed], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlvVyit7c%253D&md5=b4212a1dd1365aedfd384e685afdefebThe hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral proteinLee, Choongho; Ma, Han; Hang, Julie Qi; Leveque, Vincent; Sklan, Ella H.; Elazar, Menashe; Klumpp, Klaus; Glenn, Jeffrey S.Virology (2011), 414 (1), 10-18CODEN: VIRLAX; ISSN:0042-6822. (Elsevier B.V.)The hepatitis C virus (HCV) non-structural (NS) 5A protein plays an essential role in the replication of the viral RNA by the membrane-assocd. replication complex (RC). Recently, a putative NS5A inhibitor, BMS-790052, exhibited the highest potency of any known anti-HCV compd. in inhibiting HCV replication in vitro and showed a promising clin. effect in HCV-infected patients. The precise mechanism of action for this new class of potential anti-HCV therapeutics, however, is still unclear. In order to gain further insight into its mode of action, we sought to test the hypothesis that the antiviral effect of BMS-790052 might be mediated by interfering with the functional assembly of the HCV RC. We obsd. that BMS-790052 indeed altered the subcellular localization and biochem. fractionation of NS5A. Taken together, our data suggest that NS5A inhibitors such as BMS-790052 can suppress viral genome replication by altering the proper localization of NS5A into functional RCs.
- 290Chang, W.; Mosley, R. T.; Bansal, S.; Keilman, M.; Lam, A. M.; Furman, P. A.; Otto, M. J.; Sofia, M. J. Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics. Bioorg. Med. Chem. Lett. 2012, 22, 2938– 2942, DOI: 10.1016/j.bmcl.2012.02.051[Crossref], [PubMed], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XktV2qtLk%253D&md5=513fc896ce045cbf1a236d75bb75b29cInhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimeticsChang, Wonsuk; Mosley, Ralph T.; Bansal, Shalini; Keilman, Meg; Lam, Angela M.; Furman, Phillip A.; Otto, Michael J.; Sofia, Michael J.Bioorganic & Medicinal Chemistry Letters (2012), 22 (8), 2938-2942CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The HCV non-structural protein NS5A has been established as a viable target for the development of direct acting antiviral therapy. From computational modeling studies strong intra-mol. hydrogen bonds were a common structural moiety within known NS5A inhibitors that have low pico-molar replicon potency. Efforts to reproduce these γ-turn-like substructures provided a novel NS5A inhibitor based on a fluoro-olefin isostere. This fluoro-olefin contg. inhibitor exhibited picomolar activity (EC50 = 79 pM) against HCV genotype 1b replicon without measurable cytotoxicity. This level of activity is comparable to the natural peptide-based inhibitors currently under clinic evaluation, and demonstrates that a peptidomimetic approach can serve as a useful strategy to produce potent and structurally unique inhibitors of HCV NS5A.
- 291Evelyn, C. R.; Bell, J. L.; Ryu, J. G.; Wade, S. M.; Kocab, A.; Harzdorf, N. L.; Showalter, H. D. H.; Neubig, R. R.; Larsen, S. D. Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423. Bioorg. Med. Chem. Lett. 2010, 20, 665– 672, DOI: 10.1016/j.bmcl.2009.11.056[Crossref], [PubMed], [CAS], Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsF2iur%252FO&md5=e931712238b9376b45c6e40daac3fda8Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423Evelyn, Chris R.; Bell, Jessica L.; Ryu, Jenny G.; Wade, Susan M.; Kocab, Andrew; Harzdorf, Nicole L.; Showalter, H. D. Hollis; Neubig, Richard R.; Larsen, Scott D.Bioorganic & Medicinal Chemistry Letters (2010), 20 (2), 665-672CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)We recently identified bis(amide) CCG-1423 (1) as a novel inhibitor of RhoA/C-mediated gene transcription that is capable of inhibiting invasion of PC-3 prostate cancer cells in a Matrigel model of metastasis. An initial structure-activity relationship study focusing on bioisosteric replacement of the amides and conformational restriction identified two compds., 4g and 8, with improved selectivity for inhibition of RhoA/C-mediated gene transcription and attenuated cytotoxicity relative to 1. Both compds. were also capable of inhibiting cell invasion with equal efficacy to 1 but with less attendant cytotoxicity.
- 292Canales, E.; Carlson, J. S.; Appleby, T.; Fenaux, M.; Lee, J.; Tian, Y.; Tirunagari, N.; Wong, M.; Watkins, W. J. Tri-substituted acylhydrazines as tertiary amide bioisosteres: HCV NS5B polymerase inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 4288– 4292, DOI: 10.1016/j.bmcl.2012.05.025[Crossref], [PubMed], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotVejtrY%253D&md5=5b3556448780b77b93743f2bf707c995Tri-substituted acylhydrazines as tertiary amide bioisosteres: HCV NS5B polymerase inhibitorsCanales, Eda; Carlson, Joseph S.; Appleby, Todd; Fenaux, Martijn; Lee, Johnny; Tian, Yang; Tirunagari, Neeraj; Wong, Melanie; Watkins, William J.Bioorganic & Medicinal Chemistry Letters (2012), 22 (13), 4288-4292CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The use of a tri-substituted acylhydrazine as an isostere of a tertiary amide was explored in a series of HCV NS5B thumb site II inhibitors. Direct replacement generated an analog with similar conformational and physicochem. properties. The series was extended to produce compds. with potent binding affinities and encouraging levels of cellular potency.
- 293Trippier, P. C. Selecting good ‘drug-like’ properties to optimize small molecule blood-brain barrier penetration. Curr. Med. Chem. 2016, 23, 1392– 1407, DOI: 10.2174/0929867323666160405112353[Crossref], [PubMed], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XptVWlurw%253D&md5=8edfbeec9c34759a5ecc809b645794d5Selecting Good 'Drug-Like' Properties to Optimize Small Molecule Blood-Brain Barrier PenetrationTrippier, Paul C.Current Medicinal Chemistry (2016), 23 (14), 1392-1407CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)The success rate to achieve clin. approval of drugs developed to treat diseases of the central nervous system (CNS) is the lowest of all disease indications. A large contributor to this poor success rate is failure of small mols. to pass through the blood-brain barrier (BBB), a barrier composed of capillary endothelial cells connected by tight junctions that functions to extrude xenobiotics from the brain. Designing small mols. to be BBB penetrant has been the subject of intensive research and has resulted in a series of guidelines to attain the best possible chances of BBB penetration. This review will analyze the current state of thinking in ranking the importance of various physicochem. properties required to select BBB penetrant mols., describe model systems to det. BBB penetration, summarize data anal. methods and provide an outlook on further developments in the field.
- 294Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fischer, H.; Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Oxetanes as promising modules in drug discovery. Angew. Chem., Int. Ed. 2006, 45, 7736– 7739, DOI: 10.1002/anie.200602343[Crossref], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht12rsrfK&md5=cd500bc1cff28f16b9dc3a2f1b9895bfOxetanes as promising modules in drug discoveryWuitschik, Georg; Rogers-Evans, Mark; Mueller, Klaus; Fischer, Holger; Wagner, Bjoern; Schuler, Frnaz; Polonnchuk, Liudmila; Carreira, Erick M.Angewandte Chemie, International Edition (2006), 45 (46), 7736-7739CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Introduction of an oxetane ring results in remarkably improved physico- and biochem. properties of the underlying scaffold. The oxetane ring confers enhanced soly., reduces the metabolic degrdn., lipophilicity, and amphiphilicity, and modulates the basicity of a nearby amine group.
- 295Bull, J. A.; Croft, R. A.; Davis, O. A.; Doran, R.; Morgan, K. F. Oxetanes: recent advances in synthesis, reactivity, and medicinal chemistry. Chem. Rev. 2016, 116, 12150– 12233, DOI: 10.1021/acs.chemrev.6b00274[ACS Full Text], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFWqtrfN&md5=a65f330a32a3e131ec5b60280382bfe4Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal ChemistryBull, James A.; Croft, Rosemary A.; Davis, Owen A.; Doran, Robert; Morgan, Kate F.Chemical Reviews (Washington, DC, United States) (2016), 116 (19), 12150-12233CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. The four-membered oxetane ring has been increasingly exploited for its contrasting behaviors: its influence on physicochem. properties as a stable motif in medicinal chem. and its propensity to undergo ring-opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivs. This review takes an overview of the literature for the synthesis of oxetane derivs., concg. on advances in the last five years up to the end of 2015. These methods are clustered by strategies for prepn. of the ring and further derivatization of preformed oxetane-contg. building blocks. Examples of the use of oxetanes in medicinal chem. are reported, including a collation of oxetane derivs. appearing in recent patents for medicinal chem. applications. Finally, examples of oxetane derivs. in ring-opening and ring-expansion reactions are described.
- 296McLaughlin, M.; Yazaki, R.; Fessard, T. C.; Carreira, E. M. Oxetanyl peptides: novel peptidomimetic modules for medicinal chemistry. Org. Lett. 2014, 16, 4070– 4073, DOI: 10.1021/ol501590n[ACS Full Text], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1ansr7K&md5=120bb06c0cdd08cd83be7f2e56ad0f8cOxetanyl Peptides: Novel Peptidomimetic Modules for Medicinal ChemistryMcLaughlin, Martin; Yazaki, Ryo; Fessard, Thomas C.; Carreira, Erick M.Organic Letters (2014), 16 (16), 4070-4073CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)The synthesis of novel oxetanyl peptides, where the amide bond is replaced by a non-hydrolyzable oxetanylamine fragment, is reported. This new class of pseudo-dipeptides with the same H-bond donor/acceptor pattern found in proteins expands the repertoire of peptidomimetics.
- 297Powell, N. H.; Clarkson, G. J.; Notman, R.; Raubo, P.; Martin, N. G.; Shipman, M. Synthesis and structure of oxetane containing tripeptide motifs. Chem. Commun. 2014, 50, 8797– 8800, DOI: 10.1039/C4CC03507K[Crossref], [PubMed], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVGnsLrK&md5=1838a361bfebb38658c8f3a2c2855934Synthesis and structure of oxetane containing tripeptide motifsPowell, Nicola H.; Clarkson, Guy J.; Notman, Rebecca; Raubo, Piotr; Martin, Nathaniel G.; Shipman, MichaelChemical Communications (Cambridge, United Kingdom) (2014), 50 (63), 8797-8800CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A new class of peptidomimetic is reported in which one of the amide C:O bonds of the peptide backbone is replaced by an oxetane ring. They are synthesized by conjugate addn. of various α-amino esters to a 3-(nitromethylene)oxetane, redn. of the nitro group and further coupling with N-Z protected amino acids to grow the peptide chain. Structural insights are provided by X-ray diffraction and mol. dynamics simulations.
- 298Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Muller, K. Oxetanes in drug discovery: structural and synthetic insights. J. Med. Chem. 2010, 53, 3227– 3246, DOI: 10.1021/jm9018788[ACS Full Text], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjvFKjt7s%253D&md5=e95742d38e933c2fb0d76d638ccc773cOxetanes in Drug Discovery: Structural and Synthetic InsightsWuitschik, Georg; Carreira, Erick M.; Wagner, Bjorn; Fischer, Holger; Parrilla, Isabelle; Schuler, Franz; Rogers-Evans, Mark; Muller, KlausJournal of Medicinal Chemistry (2010), 53 (8), 3227-3246CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The use of oxetanes as replacements for gem-di-Me or carbonyl groups and their effects on the aq. soly., lipophilicity, metabolic stability, and conformation for various compds. are studied; methods for the prepn. of a variety of substituted oxetanes are given. The magnitude of changes in properties and in metabolic stability with oxetane substitution depends on the structural context; for example, substitution of a gem-di-Me group with an oxetane, aq. soly. may increase by a factor of 4 to more than 4000 while reducing the rate of metabolic degrdn. in most cases. Incorporation of an oxetane into an aliph. chain increases in some cases the preference for synclinal conformations rather than antiplanar conformations of the chain. Spirocyclic oxetanes such as an oxazaspiroheptane resemble commonly used fragments in drug discovery, such as morpholines, and in some cases increase aq. soly. more effectively than morpholines. An improved chemoselective oxidn. of 3-oxetanol to 3-oxetanone is disclosed; olefination of 3-oxetanone by a variety of methods yields alkylideneoxetanes I [R = (EtO)2P(:O), OHC, O2N, EtO2C, NC, PhO2S, MeCO, 1-(4-chlorophenyl)-1-cyclobutanecarbonyl]. I (R = EtO2C, OHC, O2N) undergo addn. reactions with nucleophiles such as amines, carbonyl compds., and arylboronic acids to give oxetanes such as II. The crystal structures of a variety of oxetanes are detd.
- 299Beadle, J. D.; Powell, N. H.; Raubo, P.; Clarkson, G. J.; Shipman, M. Synthesis of oxetane- and azetidine-containing spirocycles related to the 2,5-diketopiperazine framework. Synlett 2015, 27, 169– 172, DOI: 10.1055/s-0035-1560593
- 300Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 2009, 52, 6752– 6756, DOI: 10.1021/jm901241e[ACS Full Text], [CAS], Google Scholar300https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1KjtLvN&md5=4ca92c30c17c53d77ad376719bad951eEscape from Flatland: Increasing Saturation as an Approach to Improving Clinical SuccessLovering, Frank; Bikker, Jack; Humblet, ChristineJournal of Medicinal Chemistry (2009), 52 (21), 6752-6756CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The medicinal chem. community has become increasingly aware of the value of tracking calcd. phys. properties such as mol. wt., topol. polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. The authors hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose mols. to fail by steering discovery efforts toward achiral, arom. compds. The authors have proposed two simple and interpretable measures of the complexity of mols. prepd. as potential drug candidates. The first is carbon bond satn. as defined by fraction Sp3 (Fsp3) where Fsp3 = (no. of Sp3 hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the mol. The authors demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compds. transition from discovery, through clin. testing, to drugs. To explain these observations, the authors further demonstrate that satn. correlates with soly., an exptl. phys. property important to success in the drug discovery setting.
- 301Trippier, P. C.; McGuigan, C. Boronic acids in medicinal chemistry: anticancer, antibacterial and antiviral applications. MedChemComm 2010, 1, 183– 198, DOI: 10.1039/c0md00119h[Crossref], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtVymt7vO&md5=27d8b40712213a0eaab370f3010033cfBoronic acids in medicinal chemistry: anticancer, antibacterial and antiviral applicationsTrippier, Paul C.; McGuigan, ChristopherMedChemComm (2010), 1 (3), 183-198CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A review. In 2003, bortezomib, a first-in-class therapeutic, gained approval from the US Federal Drug Administration for the treatment of relapsed multiple myeloma and mantle cell lymphoma. Approval in the UK, for multiple myeloma, followed in 2006. Bortezomib contains a boronic acid, a functional group that has become increasingly more commonplace within the medicinal chem. literature. The introduction of this drug has sparked a renewed interest in the investigation of boronic acids as drugs for a wide range of diseases. This review will guide the reader through the most recent developments in this field, by considering in turn, the biol. target's amenable to the action of boronic acids.
- 302Fernandes, G. F. S.; Denny, W. A.; Dos Santos, J. L. Boron in drug design: recent advances in the development of new therapeutic agents. Eur. J. Med. Chem. 2019, 179, 791– 804, DOI: 10.1016/j.ejmech.2019.06.092[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtleju7fE&md5=52c7677a4b6213be8a03b48c3981bba4Boron in drug design: Recent advances in the development of new therapeutic agentsFernandes, Guilherme Felipe Santos; Denny, William Alexander; Dos Santos, Jean LeandroEuropean Journal of Medicinal Chemistry (2019), 179 (), 791-804CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Advances in the field of boron chem. have expanded the application of this element in Medicinal Chem. Boron-contg. compds. represent a new class for medicinal chemists to use in their drug designs. Bortezomib, a dipeptide boronic acid approved by the FDA in 2003 for treatment of multiple myeloma, paved the way for the discovery of new boron-contg. compds. After its approval, two other boron-contg. compds. have been approved, tavaborole for the treatment of onychomycosis and crisaborole for the treatment of mild to moderate atopic dermatitis. A no. of boron-contg. compds. have been described and evaluated for a plethora of therapeutic applications. The present review is intended to highlight the recent advances related to boron-contg. compds. and their therapeutic applications. Here, we focused only in those most biol. active compds. with proven in vitro and/or in vivo efficacy in the therapeutic area published in the last years.
- 303Malde, A. K.; Khedkar, S. A.; Coutinho, E. C. The B(OH)–NH analog is a surrogate for the amide bond (CO–NH) in peptides: an ab initio Study. J. Chem. Theory Comput. 2007, 3, 619– 627, DOI: 10.1021/ct600256s[ACS Full Text], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xhtlekt73I&md5=936a42f8641fbf6ce95efc54918a9596The B(OH)-NH Analog Is a Surrogate for the Amide Bond (CO-NH) in Peptides: An ab Initio StudyMalde, Alpeshkumar K.; Khedkar, Santosh A.; Coutinho, Evans C.Journal of Chemical Theory and Computation (2007), 3 (2), 619-627CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)The conformational preferences of N-methyl-methylboronamide (NMB), a B(OH)-NH analog of the amide CO-NH in natural peptides, were studied at the Hartree-Fock; Becke's three-parameter exchange functional and the gradient-cor. functional of Lee, Yang, and Parr; and 2nd-order Moller-Plesset levels of theory with the 6-31+G* basis set. The min., saddle points, and rotation barriers on the potential energy surface of NMB were located and the energy barriers estd. Besides the global min., there are three local min. within 2.0 kcal mol-1 of the global min. characterized by specific ω and τ torsion values. The energy barriers for rotation about the ω angle are 16.4-18.8 kcal mol-1 and are a consequence of the double-bond character of the B-N bond as revealed by natural bond orbitals calcns. The ω angle and the ω rotation barrier are nearly the same as those seen in natural peptides. The τ rotation barriers (B-O bond) are relatively low because of the single-bond character of the B-O bond. Ala-BON, the Ala-dipeptide derived from NMB, was constructed as a model peptide to study the conformational preferences about the φ and ψ torsion angles. The study reveals a strong preference for α-helix, type-II β-turn, 2.27 ribbon, and antiparallel β-sheet conformations, and mirror images of both type-II β-turn and 2.27 ribbon motifs whose φ and ψ values fall in the disfavored regions of the Ramachandran map. Thus, the replacement of the carbonyl group by B-OH retains the geometry and barrier around the ω angle and induces a strong preference for regular secondary structure motifs and also structures with pos. φ values. This makes the B(OH)-NH analog an important surrogate for the peptide bond, with the addnl. advantage of stability to proteolytic enzymes.
- 304Ramesh, R.; Reddy, D. S. Quest for novel chemical entities through incorporation of silicon in drug scaffolds. J. Med. Chem. 2018, 61, 3779– 3798, DOI: 10.1021/acs.jmedchem.7b00718[ACS Full Text], [CAS], Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1KnsbvM&md5=fa3da0fddb955d156d410eb68030e78aQuest for Novel Chemical Entities through Incorporation of Silicon in Drug ScaffoldsRamesh, Remya; Reddy, D. SrinivasaJournal of Medicinal Chemistry (2018), 61 (9), 3779-3798CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In order to optimize a lead mol. for further development, bioisosteric replacements are generally adopted as one of the strategies. Silicon appears to be the right choice as a carbon isostere because of the similarity in chem. properties. Silicon can be strategically introduced in a mol. to modulate its druglike properties, providing medicinal chemists with an unconventional strategy for replacing a carbon atom. Silicon can also be introduced to replace other heteroatoms and can act as a surrogate of functional groups such as olefin and amide as well. The present Perspective focuses on the opportunities that silicon incorporation offers in drug discovery, with an emphasis on case studies where introduction of silicon has created a benefit over its analog. We have tried to highlight all the recent developments in the field and briefly discuss the challenges assocd. with them.
- 305Chen, C. A.; Sieburth, S. M.; Glekas, A.; Hewitt, G. W.; Trainor, G. L.; Erickson-Viitanen, S.; Garber, S. S.; Cordova, B.; Jeffry, S.; Klabe, R. M. Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV protease. Chem. Biol. 2001, 8, 1161– 1166, DOI: 10.1016/S1074-5521(01)00079-5[Crossref], [PubMed], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XisFai&md5=1a1c62fd91039e43f4f2f211811cdde4Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV proteaseChen, Chien-An; Sieburth, Scott McN.; Glekas, Athanasios; Hewitt, Gregory W.; Trainor, George L.; Erickson-Viitanen, Susan; Garber, Sena S.; Cordova, Beverly; Jeffry, Susan; Klabe, Ronald M.Chemistry & Biology (2001), 8 (12), 1161-1166CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Science Ltd.)Background: Silicon is the element most similar to carbon, and bioactive organosilanes have therefore been of longstanding interest. Design of bioactive organosilanes has often involved a systematic replacement of a bioactive mol.'s stable carbon atoms with silicon. Silanediols, which are best known as unstable precursors of the robust and ubiquitous silicone polymers, have the potential to mimic an unstable carbon, the hydrated carbonyl. As a bioisostere of the tetrahedral intermediate of amide hydrolysis, a silanediol could act as a transition state analog inhibitor of protease enzymes. Results: Silanediol analogs of a carbinol-based inhibitor of the HIV protease were prepd. as single enantiomers, with up to six stereogenic centers. As inhibitors of this aspartic protease, the silanediols were nearly equiv. to both their carbinol analogs and indinavir, a current treatment for AIDS, with low nanomolar Ki values. IC90 data from a cell culture assay mirrored the Ki data, demonstrating that the silanediols can also cross cell membranes and deliver their antiviral effects. Conclusions: In their first evaluation as inhibitors of an aspartic protease, silanediol peptidomimetics have been found to be nearly as potent as currently available pharmaceutical agents, in enzyme and cell protection assays. These neutral, cell-permeable transition state analogs therefore provide a novel foundation for the design of therapeutic agents.
- 306Madsen, A. S.; Kristensen, H. M. E.; Lanz, G.; Olsen, C. A. The effect of various zinc binding groups on inhibition of histone deacetylases 1–11. ChemMedChem 2014, 9, 614– 626, DOI: 10.1002/cmdc.201300433[Crossref], [PubMed], [CAS], Google Scholar306https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitVWjur3N&md5=4cc4f341ecb112034d26aeb668f3332fThe Effect of Various Zinc Binding Groups on Inhibition of Histone Deacetylases 1-11Madsen, Andreas S.; Kristensen, Helle M. E.; Lanz, Gyrithe; Olsen, Christian A.ChemMedChem (2014), 9 (3), 614-626CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Histone deacetylases (HDACs) have the ability to cleave the acetyl groups of ε-N-acetylated lysine residues in a variety of proteins. Given that human cells contain thousands of different acetylated lysine residues, HDACS may regulate a wide variety of processes including some implicated in conditions such as cancer and neurodegenerative disorders. Herein we report the synthesis and in vitro biochem. profiling of a series of compds., including known inhibitors as well as novel chemotypes, that incorporate putative new zinc binding domains. By evaluating the compd. collection against all 11 recombinant human HDACs, we found that the trifluoromethyl ketone functionality provides potent inhibition of all four subclasses of the Zn2+-dependent HDACs. Potent inhibition was obsd. with two different scaffolds, demonstrating the efficiency of the trifluoromethyl ketone moiety as a zinc binding motif. Interestingly, we also identified silanediol as a zinc binding group with potential for future development of non-hydroxamate class I and class IIb HDAC inhibitors.
- 307Slusarczyk, M.; Serpi, M.; Pertusati, F. Phosphoramidates and phosphonamidates (ProTides) with antiviral activity. Antivir. Chem. Chemother. 2018, 26, 1– 31, DOI: 10.1177/2040206618775243